U.S. patent application number 14/391502 was filed with the patent office on 2015-04-09 for compounds which inhibit neuronal exocytosis.
The applicant listed for this patent is Lubrizol Advanced Materials, Inc.. Invention is credited to N ria Alminana Domenech, Cristina Carreno Serraima, Raquel Delgado Gonzalez, Gregorio Fernandez Ballester, Antonio Vicente Ferrer Montiel, Jose Maria Garcia Anton.
Application Number | 20150098989 14/391502 |
Document ID | / |
Family ID | 49327143 |
Filed Date | 2015-04-09 |
United States Patent
Application |
20150098989 |
Kind Code |
A1 |
Ferrer Montiel; Antonio Vicente ;
et al. |
April 9, 2015 |
COMPOUNDS WHICH INHIBIT NEURONAL EXOCYTOSIS
Abstract
Compounds of general formula (I):
R.sub.1--W.sub.n--X.sub.m-AA.sub.1-AA.sub.2-AA.sub.3-AA.sub.4-AA.sub.5-AA-
.sub.6-AA.sub.7-Y.sub.p--Z.sub.q--R.sub.2, their stereoisomers,
mixtures thereof and/or their cosmetically or pharmaceutically
acceptable salts, preparation processes, cosmetic or pharmaceutical
compositions which contain them and their use in medicine,
particularly in the treatment and/or prevention of pain,
inflammation, itching, neurological, compulsive and/or
neuropsychiatric diseases and/or disorders and in processes of
treatment and/or care of the skin, hair and/or mucous membranes
mediated by neuronal exocytosis.
Inventors: |
Ferrer Montiel; Antonio
Vicente; (Alicante, ES) ; Fernandez Ballester;
Gregorio; (Murcia, ES) ; Garcia Anton; Jose
Maria; (Barcelona, ES) ; Carreno Serraima;
Cristina; (Barcelona, ES) ; Alminana Domenech; N
ria; (Barcelona, ES) ; Delgado Gonzalez; Raquel;
(Barcelona, ES) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Lubrizol Advanced Materials, Inc. |
Cleveland |
OH |
US |
|
|
Family ID: |
49327143 |
Appl. No.: |
14/391502 |
Filed: |
April 12, 2013 |
PCT Filed: |
April 12, 2013 |
PCT NO: |
PCT/EP2013/057656 |
371 Date: |
October 9, 2014 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
61652647 |
May 29, 2012 |
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61746888 |
Dec 28, 2012 |
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Current U.S.
Class: |
424/450 ;
424/489; 424/59; 424/62; 424/65; 424/70.14; 514/17.8; 514/18.8;
514/20.7; 514/21.7; 530/329 |
Current CPC
Class: |
A61K 8/11 20130101; A61Q
19/00 20130101; A61P 43/00 20180101; A61P 17/14 20180101; C07K 7/06
20130101; A61P 17/06 20180101; A61Q 15/00 20130101; A61P 17/12
20180101; A61K 8/64 20130101; A61P 17/16 20180101; A61K 38/00
20130101; A61P 17/10 20180101; A61P 25/00 20180101; A61K 8/14
20130101; A61P 17/00 20180101 |
Class at
Publication: |
424/450 ;
530/329; 514/21.7; 424/489; 424/65; 424/62; 424/59; 424/70.14;
514/17.8; 514/20.7; 514/18.8 |
International
Class: |
C07K 7/06 20060101
C07K007/06 |
Foreign Application Data
Date |
Code |
Application Number |
Apr 13, 2012 |
EP |
12382144.9 |
Jul 27, 2012 |
EP |
12382303.1 |
Claims
1. A compound of general formula (I):
R.sub.1--W.sub.n--X.sub.m-AA.sub.1-AA.sub.2-AA.sub.3-AA.sub.4-AA.sub.5-AA-
.sub.6-AA.sub.7-Y.sub.p--Z.sub.q--R.sub.2 (I) its stereoisomers,
mixtures thereof and/or its cosmetically or pharmaceutically
acceptable salts, wherein: AA.sub.1 is selected from the group
consisting of -Arg-, -His-, -Lys-, -Gln-, -Asn-, -Glu- and -Asp-;
AA.sub.2 is selected from the group consisting of -His-, -Gln-,
-Asn-, -Glu- and -Asp-; AA.sub.3 is selected from the group
consisting of -Leu-, -Ile-, -Phe- and -Tyr-; AA.sub.4 is selected
from the group consisting of -Lys-, -His-, -Arg-, -Gln-, -Leu-,
-Ile-, -Met-, -MetO-- and -MetO.sub.2--; AA.sub.5 is selected from
the group consisting of -Arg-, -His-, -Lys-, -Gln-, -Asn-, -Glu-
and -Asp-; AA.sub.6 is selected from the group consisting of -Phe-,
-Trp-, -Ile- and -Val-; AA.sub.7 is selected from the group
consisting of -Met-, -MetO-- and -MetO.sub.2--; W, X, Y, Z are
amino acids and are independently selected from amongst themselves;
n, m, p and q are independently selected from amongst themselves
and have a value of 0 or 1; n+m+p+q is smaller than or equal to 2;
with the condition that it is not SEQ ID NO:111; R.sub.1 is
selected from the group consisting of H, a polymer derived from
polyethylene glycol, a non-cyclic substituted or unsubstituted
aliphatic group, substituted or unsubstituted alicyclyl,
substituted or unsubstituted heterocyclyl, substituted or
unsubstituted heteroarylalkyl, substituted or unsubstituted aryl,
substituted or unsubstituted aralkyl and R.sub.5--CO--, wherein
R.sub.5 is selected from the group consisting of H, a non-cyclic
substituted or unsubstituted aliphatic group, substituted or
unsubstituted alicyclyl, substituted or unsubstituted aryl,
substituted or unsubstituted aralkyl, substituted or unsubstituted
heterocyclyl and substituted or unsubstituted heteroarylalkyl;
R.sub.2 is selected from the group consisting of --NR.sub.3R.sub.4,
--OR.sub.3 and --SR.sub.3, wherein R.sub.3 and R.sub.4 are
independently selected from the group consisting of H, a polymer
derived from polyethylene glycol, a non-cyclic substituted or
unsubstituted aliphatic group, substituted or unsubstituted
alicyclyl, substituted or unsubstituted heterocyclyl, substituted
or unsubstituted heteroarylalkyl, substituted or unsubstituted
aryl, and substituted or unsubstituted aralkyl; and R.sub.1 and
R.sub.2 are not .alpha.-amino acids.
2. The compound according to claim 1, wherein AA.sub.1 is selected
from the group consisting of -Arg-, -Lys-, -Gln-, -Asn-, -Glu- and
-Asp-, AA.sub.2 is selected from the group consisting of -His-,
-Gln-, -Asn-, -Glu- and -Asp-, AA.sub.3 is selected from the group
consisting of -Leu- and -Phe-, AA.sub.4 is selected from the group
consisting of -His-, -Lys-, -Gln- and -Leu-, AA.sub.5 is selected
from the group consisting of -Arg-, -His-, -Lys-, -Gln-, -Asn-,
-Glu- and -Asp-, AA.sub.6 is selected from the group consisting of
-Trp- and -Val- and AA.sub.7 is selected from the group consisting
of -Met-, -MetO-- and -MetO.sub.2.
3. The compound according to claim 2, wherein AA.sub.4 is selected
from the group consisting of -Lys- and -Leu-, and AA.sub.6 is
-Trp-.
4. The compound according to claim 3, wherein n, m, p and q are
0.
5. The compound according to claim 2, wherein R.sub.1 is selected
from the group consisting of H, acetyl, lauroyl, myristoyl and
palmitoyl, AA.sub.1 is selected from the group consisting of
-L-Asn-, -L-Glu- and -L-Asp-, AA.sub.2 is selected from the group
consisting of -L-His- and -L-Asp-, AA.sub.3 is selected from the
group consisting of -L-Leu- and -L-Phe-, AA.sub.4 is selected from
the group consisting of -L-Lys-, -L-Gln- and -L-Leu-, AA.sub.5 is
selected from the group consisting of -L-Arg-, -L-Gln-, -L-Asn- and
-L-Asp-, AA.sub.6 is selected from the group consisting of -L-Trp-,
AA.sub.7 is selected from the group consisting of -L-Met-,
-L-MetO-- and -L-MetO.sub.2--, and R.sub.2 is selected from the
group consisting of --NR.sub.3R.sub.4 and --OR.sub.3 wherein
R.sub.3 and R.sub.4 are independently selected from H, methyl,
ethyl, hexyl, dodecyl and hexadecyl.
6. The compound according to claim 2, wherein R.sub.1 is selected
from the group consisting of H, acetyl, lauroyl, myristoyl and
palmitoyl, AA.sub.1 is -L-Glu-, AA.sub.2 is selected from the group
consisting of -L-Asn-, -L-Glu-, -L-Gln- and -L-Asp-, AA.sub.3 is
-L-Leu-, AA.sub.4 is -L-Lys-, AA.sub.5 is -L-Arg-, AA.sub.6 is
-L-Trp-, AA.sub.7 is selected from the group consisting of -L-Met-,
-L-MetO-- and -L-MetO.sub.2--, and R.sub.2 is selected from the
group consisting of --NR.sub.3R.sub.4 and --OR.sub.3 where R.sub.3
and R.sub.4 are independently selected from H, methyl, ethyl,
hexyl, dodecyl and hexadecyl.
7. The compound according to claim 5, wherein R.sub.1 is selected
from the group consisting of H, acetyl, lauroyl, myristoyl or
palmitoyl, AA.sub.1 is -L-Glu-, AA.sub.2 is -L-His-, AA.sub.3 is
-L-Leu-, AA.sub.4 is -L-Lys-, AA.sub.5 is -L-Gln-, AA.sub.6 is
-L-Trp-, AA.sub.7 is -L-Met-, -L-MetO-- or -L-MetO.sub.2-- and
R.sub.2 is --NR.sub.3R.sub.4 or --OR.sub.3 wherein R.sub.3 and
R.sub.4 are independently selected from H, methyl, ethyl, hexyl,
dodecyl and hexadecyl.
8. The compound according to claim 5, wherein R.sub.1 is selected
from the group consisting of H, acetyl, lauroyl, myristoyl or
palmitoyl, AA.sub.1 is -L-Glu-, AA.sub.2 is -L-Asp-, AA.sub.3 is
-L-Leu-, AA.sub.4 is -L-Lys-, AA.sub.5 is -L-Arg-, AA.sub.6 is
-L-Trp-, AA.sub.7 is -L-Met-, -L-MetO-- or -L-MetO.sub.2-- and
R.sub.2 is --NR.sub.3R.sub.4 or --OR.sub.3 wherein R.sub.3 and
R.sub.4 are independently selected from H, methyl, ethyl, hexyl,
dodecyl and hexadecyl.
9. The compound according to claim 5, wherein R.sub.1 is selected
from the group consisting of H, acetyl, lauroyl, myristoyl or and
palmitoyl, AA.sub.1 is -L-Asn-, AA.sub.2 is -L-His-, AA.sub.3 is
-L-Phe-, AA.sub.4 is -L-Leu-, AA.sub.5 is -L-Asn-, AA.sub.6 is
-L-Trp-, AA.sub.7 is -L-Met-, -L-MetO-- or -L-MetO.sub.2-- and
R.sub.2 is --NR.sub.3R.sub.4 or --OR.sub.3 wherein R.sub.3 and
R.sub.4 are independently selected from H, methyl, ethyl, hexyl,
dodecyl and hexadecyl.
10. The compound according to claim 5, wherein R.sub.1 is selected
from the group consisting of H, acetyl, lauroyl, myristoyl or and
palmitoyl, AA.sub.1 is -L-Asp-, AA.sub.2 is -L-His-, AA.sub.3 is
-L-Phe-, AA.sub.4 is -L-Leu-, AA.sub.5 is -L-Asp-, AA.sub.6 is
-L-Trp-, AA.sub.7 is -L-Met-, -L-MetO-- or -L-MetO.sub.2-- and
R.sub.2 is --NR.sub.3R.sub.4 or OR.sub.3 wherein R.sub.3 and
R.sub.4 are independently selected from H, methyl, ethyl, hexyl,
dodecyl and hexadecyl.
11. A cosmetic or pharmaceutical composition which comprises at
least one compound of general formula (I), its stereoisomers,
mixtures thereof and/or its cosmetically or pharmaceutically
acceptable salts, according to claim 1, together with at least one
cosmetically or pharmaceutically acceptable excipient or
adjuvant.
12. The composition according to claim 11, wherein this compound of
general formula (I), its stereoisomers, mixtures thereof and/or its
cosmetically or pharmaceutically acceptable salts, is incorporated
into a cosmetically or pharmaceutically acceptable delivery system
or sustained release system selected from the group consisting of
liposomes, mixed liposomes, oleosomes, niosomes, ethosomes,
milliparticles, microparticles, nanoparticles, solid lipid
nanoparticles, nanostructured lipid carriers, sponges,
cyclodextrins, vesicles, micelles, mixed micelles of surfactants,
surfactant-phospholipid mixed micelles, millispheres, microspheres,
nanospheres, lipospheres, millicapsules, microcapsules,
nanocapsules, microemulsions and nanoemulsions or is adsorbed on a
solid organic polymer or solid mineral support selected from the
group consisting of talc, bentonite, silica, starch and
maltodextrin.
13. The composition according to claim 11, wherein this composition
is presented in a formulation selected from the group consisting of
creams, multiple emulsions, anhydrous compositions, aqueous
dispersions, oils, milks, balsams, foams, lotions, gels, cream
gels, hydroalcoholic solutions, hydroglycolic solutions, hydrogels,
liniments, sera, soaps, shampoos, conditioners, serums,
polysaccharide films, ointments, mousses, pomades, powders, bars,
pencils, sprays, aerosols, capsules, gelatin capsules, soft
capsules, hard capsules, tablets, sugar coated tablets, pills,
powders, granules, chewing gum, solutions, suspensions, emulsions,
syrups, elixirs, jellies and gelatins.
14. The composition according to claim 11, wherein this composition
also comprises at least one cosmetically or pharmaceutically
acceptable adjuvant selected from the group consisting of agents
which inhibit neuronal exocytosis, anticholinergic agents, agents
which inhibit muscular contraction, anti-aging agents, anti-wrinkle
agents, antiperspirant agents, anti-inflammatory agents and/or
analgesics, anti-itching agents, calming agents, anesthetic agents,
inhibitors of acetylcholine-receptor aggregation, agents that
inhibit acetylcholinesterase, skin relaxant agents, melanin
synthesis stimulating or inhibiting agents, whitening or
depigmenting agents, propigmenting agents, self-tanning agents,
NO-synthase inhibiting agents, 5.alpha.-reductase inhibiting
agents, lysyl- and/or prolyl hydroxylase inhibiting agents,
antioxidants, free radical scavengers and/or agents against
atmospheric pollution, reactive carbonyl species scavengers,
anti-glycation agents, antihistamine agents, antiviral agents,
antiparasitic agents, emulsifiers, emollients, organic solvents,
liquid propellants, skin conditioners, humectants, substances that
retain moisture, alpha hydroxy acids, beta hydroxy acids,
moisturizers, epidermal hydrolytic enzymes, vitamins, amino acids,
proteins, pigments, colorants, dyes, biopolymers, gelling polymers,
thickeners, surfactants, softening agents, emulsifiers, binding
agents, preservatives, agents able to reduce or treat bags under
the eyes, exfoliating agents, keratolytic agents, flaking agents,
antimicrobial agents, antifungal agents, fungistatic agents,
bactericidal agents, bacteriostatic agents, agents stimulating the
synthesis of dermal or epidermal macromolecules and/or capable of
inhibiting their degradation, collagen synthesis-stimulating
agents, elastin synthesis-stimulation agents, decorin
synthesis-stimulation agents, laminin synthesis-stimulation agents,
defensin synthesis-stimulating agents, chaperone
synthesis-stimulating agents, cAMP synthesis-stimulating agents,
AQP-3 modulating agents, aquaporin synthesis modulating agents,
proteins from the aquaporin family, hyaluronic acid
synthesis-stimulating agents, glycosaminoglycan
synthesis-stimulating agents, fibronectin synthesis-stimulating
agents, sirtuin synthesis-stimulating agents, sirtuin activating
agents, heat shock proteins, heat shock protein
synthesis-stimulating agents, agents stimulating the synthesis of
lipids and components of the stratum corneum, ceramides, fatty
acids, agents that inhibit collagen degradation, matrix
metalloproteinase inhibitory agents, agents that inhibit elastin
degradation, agents that inhibit serine proteases, agents
stimulating fibroblast proliferation, agents stimulating
keratinocyte proliferation, agents stimulating adipocyte
proliferation, agents stimulating melanocyte proliferation, agents
stimulating keratinocyte differentiation, agents stimulating or
delaying adipocyte differentiation, antihyperkeratosis agents,
comedolytic agents, anti-psoriasis agents, DNA repair agents, DNA
protecting agents, stabilizers, agents for the treatment and/or
care of sensitive skin, firming agents, anti-stretch mark agents,
binding agents, agents regulating sebum production, lipolytic
agents or agents stimulating lipolysis, adipogenic agents, agents
modulating PGC-1.alpha. expression, agents modulating PPAR.gamma.,
agents which increase or reduce the triglyceride content of
adipocytes, anti-cellulite agents, agents which inhibit the
activity of PAR-2, agents stimulating healing, coadjuvant healing
agents, agents stimulating reepithelialization, coadjuvant
reepithelialization agents, cytokine growth factors, agents acting
on capillary circulation and/or microcirculation, agents
stimulating angiogenesis, agents that inhibit vascular
permeability, venotonic agents, agents acting on cell metabolism,
agents to improve dermal-epidermal junction, agents inducing hair
growth, hair growth inhibiting or retardant agents, hair loss
retardant agents, preservatives, perfumes, cosmetic and/or
absorbent and/or body odor masking deodorants, chelating agents,
plant extracts, essential oils, marine extracts, agents obtained
from a biotechnological process, mineral salts, cell extracts,
sunscreens and organic or mineral photoprotective agents active
against ultraviolet A and/or B rays and/or infrared A rays, and
mixtures thereof.
15.-19. (canceled)
20. A method of treatment and/or delaying or hindering of pain,
inflammation, itching, hyperhidrosis and/or of neurological,
compulsive and/or neuropsychiatric diseases and/or disorders which
are improved by the inhibition of neuronal exocytosis selected from
the group consisting of muscular spasticity, dystonia, focal
dystonia, blepharospasm, torsion dystonia, cervical dystonia or
torticollis, laryngeal dystonia or spasmodic dysphonia,
oromandibular dystonia, extremity dystonia, writer's cramp,
musician's cramp, foot dystonia, bruxism, facial scoliosis,
hemifacial spasm, tics, strabismus, segmentary dystonia, Meige's
syndrome, multifocal dystonia, hemidystonia, dopamine-responsive
dystonia, Segawa's dystonia, trembling, Parkinson's disease,
nervous impingements, Alzheimer's disease and Tourette's syndrome,
which comprises the administration to a mammal's body of a
pharmaceutically effective quantity of at least one compound of
general formula (I),
R.sub.1--W.sub.n--X.sub.m-AA.sub.1-AA.sub.2-AA.sub.3-AA.sub.4-AA.sub.5-AA-
.sub.6-AA.sub.7-Y.sub.p--Z.sub.q--R.sub.2 (I) its stereoisomers,
mixtures thereof and/or its cosmetically or pharmaceutically
acceptable salts, wherein: AA.sub.1 is selected from the group
consisting of -Arg-, -His-, -Lys-, -Gln-, -Asn-, -Glu- and -Asp-;
AA.sub.2 is selected from the group consisting of -His-, -Gln-,
-Asn-, -Glu- and -Asp-; AA.sub.3 is selected from the group
consisting of -Leu-, -Ile-, -Phe- and -Tyr-; AA.sub.4 is selected
from the group consisting of -Lys-, -His-, -Arg-, -Gln-, -Leu-,
-Ile-, -Met-, -MetO-- and -MetO.sub.2--; AA.sub.5 is selected from
the group consisting of -Arg-, -His-, -Lys-, -Gln-, -Asn-, -Glu-
and -Asp-; AA.sub.6 is selected from the group consisting of -Phe-,
-Trp-, -Ile- and -Val-; AA.sub.7 is selected from the group
consisting of -Met-, -MetO-- and -MetO.sub.2--; W, X, Y, Z are
amino acids and are independently selected from among themselves;
n, m, p and q are independently selected from amongst themselves
and have a value of 0 or 1; n+m+p+q is smaller than or equal to 2;
R.sub.1 is selected from the group consisting of H, a polymer
derived from polyethylene glycol, a non-cyclic substituted or
unsubstituted aliphatic group, substituted or unsubstituted
alicyclyl, substituted or unsubstituted heterocyclyl, substituted
or unsubstituted heteroarylalkyl, substituted or unsubstituted
aryl, substituted or unsubstituted aralkyl and R.sub.5--CO--,
wherein R.sub.5 is selected from the group consisting of H, a
non-cyclic substituted or unsubstituted aliphatic group,
substituted or unsubstituted alicyclyl, substituted or
unsubstituted aryl, substituted or unsubstituted aralkyl,
substituted or unsubstituted heterocyclyl and substituted or
unsubstituted heteroarylalkyl; R.sub.2 is selected from the group
consisting of --NR.sub.3R.sub.4, --OR.sub.3 and --SR.sub.3, wherein
R.sub.3 and R.sub.4 are independently selected from the group
consisting of H, a polymer derived from polyethylene glycol, a
non-cyclic substituted or unsubstituted aliphatic group,
substituted or unsubstituted alicyclyl, substituted or
unsubstituted heterocyclyl, substituted or unsubstituted
heteroarylalkyl, substituted or unsubstituted aryl, and substituted
or unsubstituted aralkyl; and R.sub.1 and R.sub.2 are not
.alpha.-amino acids.
21. A method of treatment and/or care of the skin, hair and/or
mucous membranes which comprises the administration, to skin, hair
and/or mucous membranes, of a cosmetically or pharmaceutically
effective quantity of at least one compound of general formula (I),
R.sub.1--W.sub.n--X.sub.m-AA.sub.1-AA.sub.2-AA.sub.3-AA.sub.4-AA.sub.5-AA-
.sub.6-AA.sub.7-Y.sub.p--Z.sub.q--R.sub.2 (I) its stereoisomers,
mixtures thereof and/or its cosmetically or pharmaceutically
acceptable salts, wherein: AA.sub.1 is selected from the group
consisting of -Arg-, -His-, -Lys-, -Gln-, -Asn-, -Glu- and -Asp-;
AA.sub.2 is selected from the group consisting of -His-, -Gln-,
-Asn-, -Glu- and -Asp-; AA.sub.3 is selected from the group
consisting of -Leu-, -Ile-, -Phe- and -Tyr-; AA.sub.4 is selected
from the group consisting of -Lys-, -His-, -Arg-, -Gln-, -Leu-,
-Ile-, -Met-, -MetO-- and -MetO.sub.2--; AA.sub.5 is selected from
the group consisting of -Arg-, -His-, -Lys-, -Gln-, -Asn-, -Glu-
and -Asp-; AA.sub.6 is selected from the group consisting of -Phe-,
-Trp-, -Ile- and -Val-, AA.sub.7 is selected from the group
consisting of -Met-, -MetO-- and -MetO.sub.2--; W, X, Y, Z are
amino acids and are independently selected from among themselves;
n, m, p and q are independently selected from amongst themselves
and have a value of 0 or 1; n+m+p+q is smaller than or equal to 2;
R.sub.1 is selected from the group consisting of H, a polymer
derived from polyethylene glycol, a non-cyclic substituted or
unsubstituted aliphatic group, substituted or unsubstituted
alicyclyl, substituted or unsubstituted heterocyclyl, substituted
or unsubstituted heteroarylalkyl, substituted or unsubstituted
aryl, substituted or unsubstituted aralkyl and R.sub.5--CO--,
wherein R.sub.5 is selected from the group consisting of H, a
non-cyclic substituted or unsubstituted aliphatic group,
substituted or unsubstituted alicyclyl, substituted or
unsubstituted aryl, substituted or unsubstituted aralkyl,
substituted or unsubstituted heterocyclyl and substituted or
unsubstituted heteroarylalkyl; R.sub.2 is selected from the group
consisting of --NR.sub.3R.sub.4, --OR.sub.3 and --SR.sub.3, wherein
R.sub.3 and R.sub.4 are independently selected from the group
consisting of H, a polymer derived from polyethylene glycol, a
non-cyclic substituted or unsubstituted aliphatic group,
substituted or unsubstituted alicyclyl, substituted or
unsubstituted heterocyclyl, substituted or unsubstituted
heteroarylalkyl, substituted or unsubstituted aryl, and substituted
or unsubstituted aralkyl; and R.sub.1 and R.sub.2 are not
.alpha.-amino acids.
22. The method according to claim 21, wherein the treatment and/or
care of the skin, hair and/or mucous membranes is a treatment of
aging and/or photoaging, treatment of wrinkles and/or expression
wrinkles, treatment of perspiration, treatment and/or care of
disorders of the skin selected from the group consisting of
calluses, warts, treatment stimulating hair growth and/or delaying
or hindering of hair loss.
23. A method of inhibition of neuronal exocytosis which comprises
the administration, to a mammal's body, of a cosmetically or
pharmaceutically effective quantity of at least one compound of
general formula (I),
R.sub.1--W.sub.n--X.sub.m-AA.sub.1-AA.sub.2-AA.sub.3-AA.sub.4-AA.sub.5-AA-
.sub.6-AA.sub.7-Y.sub.p--Z.sub.q--R.sub.2 (I) its stereoisomers,
mixtures thereof and/or its cosmetically or pharmaceutically
acceptable salts, wherein: AA.sub.1 is selected from the group
consisting of -Arg-, -His-, -Lys-, -Gln-, -Asn-, -Glu- and -Asp-;
AA.sub.2 is selected from the group consisting of -His-, -Gln-,
-Asn-, -Glu- and -Asp-; AA.sub.3 is selected from the group
consisting of -Leu-, -Ile-, -Phe- and -Tyr-; AA.sub.4 is selected
from the group consisting of -Lys-, -His-, -Arg-, -Gln-, -Leu-,
-Ile-, -Met-, -MetO-- and -MetO.sub.2--; AA.sub.5 is selected from
the group consisting of -Arg-, -His-, -Lys-, -Gln-, -Asn-, -Glu-
and -Asp-; AA.sub.6 is selected from the group consisting of -Phe-,
-Trp-, -Ile- and -Val-; AA.sub.7 is selected from the group
consisting of -Met-, -MetO-- and -MetO.sub.2--; W, X, Y, Z are
amino acids and are independently selected from among themselves;
n, m, p and q are independently selected from amongst themselves
and have a value of 0 or 1; n+m+p+q is smaller than or equal to 2;
R.sub.1 is selected from the group consisting of H, a polymer
derived from polyethylene glycol, a non-cyclic substituted or
unsubstituted aliphatic group, substituted or unsubstituted
alicyclyl, substituted or unsubstituted heterocyclyl, substituted
or unsubstituted heteroarylalkyl, substituted or unsubstituted
aryl, substituted or unsubstituted aralkyl and R.sub.5--CO--,
wherein R.sub.5 is selected from the group consisting of H, a
non-cyclic substituted or unsubstituted aliphatic group,
substituted or unsubstituted alicyclyl, substituted or
unsubstituted aryl, substituted or unsubstituted aralkyl,
substituted or unsubstituted heterocyclyl and substituted or
unsubstituted heteroarylalkyl; R.sub.2 is selected from the group
consisting of --NR.sub.3R.sub.4, --OR.sub.3 and --SR.sub.3, wherein
R.sub.3 and R.sub.4 are independently selected from the group
consisting of H, a polymer derived from polyethylene glycol, a
non-cyclic substituted or unsubstituted aliphatic group,
substituted or unsubstituted alicyclyl, substituted or
unsubstituted heterocyclyl, substituted or unsubstituted
heteroarylalkyl, substituted or unsubstituted aryl, and substituted
or unsubstituted aralkyl; and R.sub.1 and R.sub.2 are not
.alpha.-amino acids.
Description
[0001] This application claims the benefit of PCT/EP2013/057656,
filed Apr. 12, 2013, and EP12382144.9, filed Apr. 13, 2012,
EP12382303.1, filed Jul. 27, 2012, U.S. Provisional Application
Ser. No. 61/652,647, filed May 29, 2012, and U.S. Provisional
Application Ser. No. 61/746,888, filed Dec. 28, 2012, from which
the PCT application claims priority, the disclosures of all of
which are incorporated herein by reference in their entireties.
FIELD OF THE INVENTION
[0002] This invention refers to compounds capable of inhibiting
neuronal exocytosis and cosmetic or pharmaceutical compositions
which contain these compounds useful in the treatment of those
conditions, disorders and/or diseases which require the inhibition
of neuronal exocytosis, such as muscle spasticity, pain,
inflammation, perspiration, facial asymmetry and/or facial
wrinkles, preferably expression wrinkles.
BACKGROUND OF THE INVENTION
[0003] Botulinum toxins (also known as botulinum neurotoxins) are
neurotoxins produced by the gram-positive bacteria Clostridium
botulinum. They act by causing the paralysis of the muscles through
the inhibition of the release of acetylcholine in the presynaptic
axon terminal of the neuromuscular junction (synaptic
transmission), thus preventing nerve transmission and muscle
contraction. The paralyzing effects of the muscles of the botulinum
toxin have been used both for therapeutic purposes as well as for
cosmetic effects. The controlled administration of the botulinum
toxin has been used for the treatment of a wide range of
conditions, disorders and diseases, such as disorders and diseases
of the urinary bladder (EP 2273976 A2), premature ejaculation (US
2011/052636 A1), priapism (U.S. Pat. No. 6,776,991 B2), ulcers and
gastroesophageal reflux (U.S. Pat. No. 7,238,357 B2), disorders and
diseases associated with hyper- and hypothyroidism (U.S. Pat. No.
6,740,321 B2), primary hyperparathyroid disorders and diseases
(U.S. Pat. No. 6,974,793 B2), perspiration and hyperhidrosis (U.S.
Pat. No. 6,974,578 B2 and U.S. Pat. No. 6,683,049 B2), inflammatory
eye disorders and diseases (U.S. Pat. No. 7,465,458 B2 and U.S.
Pat. No. 7,220,422 B2), strabismus (U.S. Pat. No. 6,841,156), otic
disorders and diseases (U.S. Pat. No. 6,265,379 B2 and U.S. Pat.
No. 6,358,926 B2), excess cerumen secretion (US 2010/028385),
neuropsychiatric disorders and diseases such as Alzheimer's,
anxiety, schizophrenia, mania, depression (U.S. Pat. No. 7,811,587
B2), different compulsive disorders and diseases such as
obsessions, compulsive skin picking, Tourette's syndrome,
trichotillomania (U.S. Pat. No. 7,393,537 B2), cerebral paralysis
(U.S. Pat. No. 6,939,852 B2), gonadotropin-related disorders and
diseases (WO 02/074327), different cancers (U.S. Pat. No. 6,139,845
B2, U.S. Pat. No. 7,838,007 B2), neoplasms (U.S. Pat. No. 7,709,440
B2), different types of pain including headaches, migraines,
fibromyalgia, arthritis or neuropathic pain among others (US
2010/266638, U.S. Pat. No. 7,811,586 B2, U.S. Pat. No. 7,704,524
B2, U.S. Pat. No. 7,704,511 B2, U.S. Pat. No. 7,468,189 B2, U.S.
Pat. No. 7,255,866 B2, U.S. Pat. No. 7,091,176 B2, U.S. Pat. No.
6,887,476 B2, U.S. Pat. No. 6,869,610 B2, U.S. Pat. No. 6,838,434
B2, U.S. Pat. No. 6,641,820 B2, U.S. Pat. No. 6,623,742 B2, U.S.
Pat. No. 6,565,870 B1, U.S. Pat. No. 6,500,436 B1, U.S. Pat. No.
6,458,365 B1, U.S. Pat. No. 6,423,319 B1, U.S. Pat. No. 6,113,915 A
and U.S. Pat. No. 5,714,468 A), neurogenic inflammation (U.S. Pat.
No. 6,063,768 B2), different disorders and diseases of the
autonomic nervous system such as otitis and sinusoidal disorders
(U.S. Pat. No. 5,766,605 A), disorders and diseases of the smooth
muscle (U.S. Pat. No. 5,437,291 A), nerve impingements (US
2003/0224019), epilepsy (U.S. Pat. No. 7,357,934 B2), dystonia
(U.S. Pat. No. 6,872,397 B2), trembling (U.S. Pat. No. 6,861,058
B2), Parkinson's disease (U.S. Pat. No. 6,620,415 B2), dizziness
(U.S. Pat. No. 7,270,287 B2), osteoporosis (WO 2011/038015),
different disorders and diseases of the skin such as calluses,
warts, ulcers and lesions on the skin (U.S. Pat. No. 8,048,423 B2,
US 2011/206731), psoriasis and dermatitis (U.S. Pat. No. 5,670,484
A), vascular hyperreactivity and rosacea (WO 2010/114828), acne (WO
03/011333), hair growth and maintenance (U.S. Pat. No. 6,299,893
B1), facial wrinkles (U.S. Pat. No. 7,255,865 B2), ptosis of the
eyebrows and forehead (US 2011/280978) or drooping mouth corners
(U.S. Pat. No. 6,358,917 B1) among others.
[0004] However, the toxicity inherent in botulinum toxin causes its
administration, in a wide range of doses, to result in undesired
secondary effects, such as immunogenic responses, cephalalgias,
nausea, paralysis or muscle weakness, respiratory failure, and in
more extreme cases even the death of the subject treated [FDA News,
Feb. 8, 2008, "FDA Notifies Public of Adverse Reactions Linked to
Botox Use"; Cote, T. R. et al. "Botulinum toxin type A injections:
Adverse events reported to the US Food and Drug Administration in
therapeutic and cosmetic cases" J. Amer. Acad. Derm. 2005, 53 (3),
407-415]. These severe secondary effects, together with the high
cost of the treatment, seriously limits the application of
botulinum toxin with therapeutic or cosmetic purposes, being
relegated to chronic applications and/or diseases for which there
is no suitable treatment. There is, therefore, a pressing need to
develop molecules which imitate the paralyzing effects of botulinum
toxins but which are equipped with much simpler and more stable
molecular structures that do not induce immune reactions, and whose
cost of production is affordable. Molecules of a peptide nature
comply with these properties.
[0005] At a molecular level, botulinum toxins are proteases which
degrade neuronal proteins that are involved in the exocytosis
mechanism activated by the calcium ion [Schiavo G. et al. "Bases
Moleculares del tetanos y del botulismo" Investigacion y Ciencia
1996, 234, 46-55; Montecucco C. and Schiavo G. "Mechanism of action
of tetanus and botulinum neurotoxins" Mol. Microbiol. 1994, 13,
1-8; Schiavo G. et al. "Tetanus and botulinum neurotoxins are zinc
proteases specific for components of the neuroexocytosis apparatus"
Ann. NY Acad. Sci. 1994, 710, 65-75]. For example, botulinum toxin
A, the most commonly used in clinics to treat the symptomatology of
spasmodic diseases and in cosmetics due to its applications in the
elimination of facial wrinkles and facial asymmetry, breaks down
the neuronal protein SNAP-25. This protein SNAP-25 plays a key role
in neurosecretion since it is involved in the formation of a
protein complex (known by the name of SNARE or fusion complex)
which manages and controls the release of acetylcholine accumulated
in vesicles. The nucleus of this fusion complex is comprised of the
proteins SNAP-25 and syntaxin, located in the presynaptic plasma
membrane, and the synaptobrevin protein of the VAMP family of
proteins, located in the vesicular plasma membrane [Calakos N. and
Scheller R. H. "Synaptic vesicle biogenesis, docking and fusion: a
molecular description" Physiol. Rev. 1996, 76, 1-29; Sutton R. B.
et al. "Crystal structure of a SNARE complex involved in synaptic
exocytosis at 2.4 .ANG. resolution" Nature 1998, 395, 347-353]. The
principal function of the fusion complex is to bring the
neurotransmitter (acetylcholine) loaded vesicle closer to and place
it in contact with the presynaptic plasma membrane [Calakos N. and
Scheller R. H. "Synaptic vesicle biogenesis, docking and fusion: a
molecular description" Physiol. Rev. 1996, 76, 1-29; Sutton R. B.
et al. "Crystal structure of a SNARE complex involved in synaptic
exocytosis at 2.4 .ANG. resolution" Nature 1998, 395, 347-353]. In
this way, in response to an increase in the concentration of
calcium, the fusion of both plasma membranes will be favored, thus
producing the release of the neurotransmitter. Therefore, this
vesicle docking and fusion protein SNARE complex constitutes a key
target for controlling neurosecretion. The truncation of any of the
proteins which form the fusion complex prevents their assembling
and, therefore, inhibits vesicle release and inhibits neuronal
exocytosis.
[0006] It is known in the prior art that certain peptides derived
from the protein sequences which form the SNARE complex are capable
of inhibiting neuronal exocytosis, such as peptides derived from
the amino and carboxy-terminal domains of the protein SNAP-25
[Apland J. P. et al. "Peptides that mimic the carboxy-terminal
domain of SNAP-25 block acetylcholine release at an aplysia
synapse" J. Appl. Toxicol. 1999, 19, Suppl. 1: S23-S26; Mehta P. P.
et al. "SNAP-25 and synaptotagmin involvement in the final
Ca.sup.2+-dependent triggering of neurotransmitter exocytosis"
Proc. Natl. Acad. Sci. USA 1996, 93, 10471-10476; Ferrer-Montiel A.
V. et al. "The 26-mer peptide released from cleavage by botulinum
neurotoxin E inhibits vesicle docking" FEBS Lett. 1998, 435, 84-88;
Gutierrez L. M. et al. "A peptide that mimics the carboxy-terminal
domain of SNAP-25 blocks Ca.sup.2+-dependent exocytosis in
chromaffin cells" FEBS Lett. 1995, 372, 39-43; Gutierrez L. M. et
al. "A peptide that mimics the C-terminal sequence of SNAP-25
inhibits secretory vesicle docking in chromaffin cells" J. Biol.
Chem. 1997, 272, 2634-2639; Blanes-Mira C et al. "Small peptides
patterned after the N-terminus domain of SNAP-25 inhibit SNARE
complex assembly and regulated exocytosis" J. Neurochem. 2004, 88,
124-135], the peptides derived from the sequence of syntaxin amino
acids [Martin F. et al. "Inhibition of insulin release by synthetic
peptides show that the H3 region at the C-terminal domain of
syntaxin-1 is crucial for Ca.sup.2+-but not for guanosine
5'-[gammathio]thriphosphate-induced secretion" Biochem. J. 1996,
320, 201-205], of the synaptobrevin [Cornille F. "Inhibition of
neurotransmitter release by synthetic prolinerich peptides shows
that the N-terminal domain of vesicle-associated membrane
protein/synaptobrevin is critical for neuro-exocytosis" J. Biol.
Chem. 1995, 270, 16826-16830], of the synaptotagmin [Mehta P. P. et
al. "SNAP-25 and synaptotagmin involvement in the final
Ca.sup.2+-dependent triggering of neurotransmitter exocytosis"
Proc. Natl. Acad. Sci. USA 1996, 93, 10471-10476] and of the
protein snapin [Ilardi J. M. et al. "Snapin: A SNARE associated
protein implicated in synaptic transmission" Nat. Neurosci. 1999,
2, 119-124]. Similarly, synthetic peptides obtained by rational
design or by searching synthetic libraries which are capable of
inhibiting neuronal exocytosis by interfering in the formation of
the SNARE complex have also been described [Blanes-Mira C. et al.
"Identification of SNARE complex modulators that inhibit exocytosis
form an .alpha.-helixconstrained combinatorial library" Biochem J.
2003, 375, 159-166].
[0007] The industrial application of this type of compounds has
been limited. The document EP 2318033 A2 describes the use of
peptides derived from SNAP-25 for the treatment of pain and
inflammation, and the document EP 1856139 A2 describes the use of
peptides derived from SNAP-25 chemically modified to increase their
bioavailability for the treatment of different diseases for which
the treatment with botulinum toxin has shown effectiveness, among
them the treatment of hyperhidrosis. Similarly, the cosmetic
industry has made significant efforts to develop compounds which
imitate the action of botulinum toxins with use in the treatment
and prevention of the formation of expression wrinkles [Blanes-Mira
C. et al. "A synthetic hexapeptide (Argireline.RTM.) with
anti-wrinkle activity" Int. J. Cosmetic Sci. 2002, 24, 303-310]. In
particular, peptides derived from the amino terminal fragment of
the protein SNAP-25 which have anti-wrinkle effects are described
in the documents EP 1180524 A1 and EP 2123673 A1, international
application WO 97/34620 also describes peptides derived from the
sequence of amino acids of the protein SNAP-25, in particular from
its carboxy-terminal region, or from the synaptobrevin or the
syntaxin capable of inhibiting neuronal exocytosis, and
international application WO 2011/048443 describes peptides derived
from the subunit c of the membrane component of V-ATPase capable of
inhibiting neuronal exocytosis through its bonding to synaptobrevin
and its potential application as anti-wrinkle treatment.
[0008] Thus, this invention provides an alternative to the existing
needs and comprises the discovery of peptide sequences not derived
from the protein SNAP-25 which are capable of inhibiting neuronal
exocytosis.
DESCRIPTION OF THE INVENTION
[0009] This invention provides an alternative to the
above-mentioned problem. Surprisingly, the authors of this
invention have found that neuronal exocytosis can be inhibited by
certain compounds not derived from the protein SNAP-25 and which
are an alternative to the existing compounds in the prior art.
These compounds are useful for the treatment and/or care of
conditions, disorders and/or diseases which improve or are
prevented by the inhibition of neuronal exocytosis.
DEFINITIONS
[0010] In order to facilitate the comprehension of this invention,
the meanings of some terms and expressions as they are used in the
context of the invention are included.
[0011] In the context of this invention "skin" is understood as the
layers which comprise it, from the uppermost layer or stratum
corneum to the lowermost layer or hypodermis, both inclusive. These
layers are composed of different types of cells such as
keratinocytes, fibroblasts, melanocytes, mastocytes, neurones
and/or adipocytes, among others. The term "skin" also comprises the
scalp.
[0012] The term "treatment", as used in the context of this
specification when it is not accompanied by the qualifications
"cosmetic, non-therapeutic", means the administration of a compound
according to the invention to alleviate or eliminate a disease or
disorder or reduce or eliminate one or more symptoms associated
with this disease or disorder. The term "treatment" also covers the
ability to alleviate or eliminate the physiological consequences of
the disease or disorder.
[0013] When the term "treatment" is accompanied by the
qualifications "cosmetic, non-therapeutic" they refer to the
application of the compound to the skin, hair and/or mucous
membranes in particular with the aim of improving the cosmetic
qualities of the skin, hair and/or mucous membranes such as and not
restricted to, their level of hydration, elasticity, firmness,
shine, tone or texture, among others. The term "care" in this
invention refers to the maintenance of the qualities of the skin,
hair and/or mucous membranes. These qualities are subject to
improvement and maintained through a cosmetic treatment and/or care
of the skin, hair and/or mucous membranes both in healthy subjects
as well as those which present diseases and/or disorders of the
skin and/or mucous membranes, such as and not restricted to, ulcers
and lesions on the skin, psoriasis, dermatitis, acne or rosacea,
among others.
[0014] The term "prevention", as used in this invention, refers to
the ability of a compound of the invention to prevent the
appearance or development of a disease or disorder before its
appearance.
[0015] In the context of this invention, the term "aging" refers to
the changes experienced by the skin with age (chronoaging) or
through exposure to the sun (photoaging) or to extreme
environmental climatic conditions of cold or wind, chemical
contaminants or pollutants, and includes all the external visible
and/or perceptible changes through touch, such as and not
restricted to, the development of discontinuities on the skin such
as wrinkles, fine lines, expression lines, stretch marks, furrows,
irregularities or roughness, increase in the size of pores, loss of
hydration, loss of elasticity, loss of firmness, loss of
smoothness, loss of the capacity to recover from deformation, loss
of resilience, sagging of the skin such as sagging cheeks, the
appearance of bags under the eyes or the appearance of a double
chin, among others, changes to the color of the skin such as marks,
reddening, bags or the appearance of hyperpigmented areas such as
age spots or freckles among others, anomalous differentiation,
hyperkeratinization, elastosis, keratosis, hair loss, orange peel
skin, loss of collagen structure and other histological changes of
the stratum corneum, of the dermis, epidermis, vascular system (for
example the appearance of spider veins or telangiectasias) or of
those tissues close to the skin, among others. The term
"photoaging" groups together the set of processes due to the
prolonged exposure of the skin to ultraviolet radiation which
result in the premature aging of the skin, and it presents the same
physical characteristics as aging, such as and not restricted to,
flaccidity, sagging, changes to the color or irregularities in the
pigmentation, abnormal and/or excessive keratinization. The sum of
several environmental factors such as exposure to tobacco smoke,
exposure to pollution, and climatic conditions such as cold and/or
wind also contributes to the aging of the skin.
[0016] In this description the abbreviations used for amino acids
follow the recommendations of the 1983 IUPAC-IUB Commission of
Biochemical Nomenclature specified in Eur. J. Biochem., (1984),
138, 937.
[0017] Thus, for example, Phe represents
NH.sub.2--CH(CH.sub.2--C.sub.5H.sub.6)--COOH, Phe- represents
NH.sub.2--CH(CH.sub.2--C.sub.5H.sub.6)--CO--, -Phe represents
--NH--CH(CH.sub.2--C.sub.5H.sub.6)--COOH and -Phe- represents
--NH--CH(CH.sub.2--C.sub.5H.sub.6)--CO--. Therefore, the hyphen,
which represents the peptide bond, eliminates the OH in the
1-carboxyl group of the amino acid (represented here in the
conventional non-ionized form) when situated to the right of the
symbol, and eliminates the H of the 2-amino group of the amino acid
when situated to the left of the symbol; both modifications can be
applied to the same symbol (see Table 1).
TABLE-US-00001 TABLE 1 Structures of the amino acid residues and
their nomenclature in one and three-letter code Name Residue Symbol
Residue Asparaginyl -Asn- N ##STR00001## Glutaminyl -Gln- Q
##STR00002## Histidyl -His- H ##STR00003## Arginyl -Arg- R
##STR00004## Lysyl -Lys- K ##STR00005## Tryptophyl -Trp- W
##STR00006## Tyrosyl -Tyr- Y ##STR00007## Phenylalanyl -Phe- F
##STR00008## Leucyl -Leu- L ##STR00009## Methionyl -Met- M
##STR00010## Valyl -Val- V ##STR00011## Isoleucyl -Ile- I
##STR00012## Glutamyl -Glu- E ##STR00013## Aspartyl -Asp- D
##STR00014## Prolyl -Pro- P ##STR00015## Glycyl -Gly- G
##STR00016## Alanyl -Ala- A ##STR00017## Methionyl (sulfoxide)
-MetO- ##STR00018## Methionyl (sulfone) -MetO.sub.2-
##STR00019##
[0018] The abbreviation "-MetO--" is used in this invention to
designate the amino acid residue methionyl(sulfoxide). The amino
acid residue methionyl(sulfoxide) can be incorporated into the
compounds of the invention using the commercial amino acid
methionine(sulfoxide) or can be obtained in situ in the compounds
of the invention by oxidation of the methionyl residue.
[0019] The abbreviation "-MetO.sub.2--" is used in this invention
to designate the amino acid residue methionyl(sulfone). The amino
acid residue methionyl(sulfone) can be incorporated into the
compounds of the invention using the commercial amino acid
methionine(sulfone) or can be obtained in situ in the compounds of
the invention by oxidation of the methionyl residue or the
methionyl(sulfoxide) residue.
[0020] The abbreviation "Ac-" is used in this description to
designate the acetyl group (CH.sub.3--CO--), the abbreviation
"Palm-" is used to designate the palmitoyl group
(CH.sub.3--(CH.sub.2).sub.14--CO--) and the abbreviation "Myr-" is
used to designate the myristoyl group
(CH.sub.3--(CH.sub.2).sub.12--CO--).
[0021] The term "non-cyclic aliphatic group" is used in this
invention to cover alkyl, alkenyl and alkynyl groups, linear or
branched.
[0022] The term "alkyl group" refers to a linear or branched
saturated group which has between 1 and 24, preferably between 1
and 16, more preferably between 1 and 14, even more preferably
between 1 and 12, yet more preferably 1, 2, 3, 4, 5 or 6 carbon
atoms and is bound to the rest of the molecule by a simple bond,
including, for example and not restricted to, methyl, ethyl,
isopropyl, isobutyl, tert-butyl, heptyl, octyl, decyl, dodecyl,
lauryl, hexadecyl, octadecyl, amyl, 2-ethylhexyl, 2-methylbutyl,
5-methylhexyl and similar.
[0023] The term "alkenyl group" refers to a group, linear or
branched, which has between 2 and 24, preferably between 2 and 16,
more preferably between 2 and 14, even more preferably between 2
and 12, yet more preferably 2, 3, 4, 5 or 6 carbon atoms, with one
or more double carbon-carbon bonds, preferably with 1, 2 or 3
double carbon-carbon bonds, conjugated or unconjugated, which is
bound to the rest of the molecule by a simple bond, including, for
example and not restricted to, the vinyl group
(--CH.sub.2.dbd.CH.sub.2), allyl (--CH.sub.2--CH.dbd.CH.sub.2),
oleyl, linoleyl and similar.
[0024] The term "alkynyl group" refers to a group, linear or
branched, which has between 2 and 24, preferably between 2 and 16,
more preferably between 2 and 14, even more preferably between 2
and 12, yet more preferably 2, 3, 4, 5 or 6 carbon atoms, with one
or more triple carbon-carbon bonds, preferably 1, 2 or 3 triple
carbon-carbon bonds, conjugated or unconjugated, which is bound to
the rest of the molecule by a simple bond, including, for example
and not restricted to, the ethynyl group, 1-propynyl, 2-propynyl,
1-butynyl, 2-butynyl, 3-butynyl, pentynyl, such as 1-pentynyl, and
similar. The alkynyl groups can also contain one or more double
carbon-carbon bonds, including for example and not restricted to,
the group but-1-en-3-ynyl, pent-4-en-1-ynyl and similar.
[0025] The term "alycyclic group" is used in this invention to
cover, for example and not restricted to, cycloalkyl or
cycloalkenyl or cycloalkynyl groups.
[0026] The term "cycloalkyl" refers to a saturated mono- or
polycyclic aliphatic group which has between 3 and 24, preferably
between 3 and 16, more preferably between 3 and 14, even more
preferably between 3 and 12, yet more preferably 3, 4, 5 or 6
carbon atoms and is bound to the rest of the molecule by a simple
bond, including, for example and not restricted to, cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, methyl
cyclohexyl, dimethyl cyclohexyl, octahydroindene,
decahydronaphthalene, dodecahydrophenalene and similar.
[0027] The term "cycloalkenyl" refers to a non-aromatic mono- or
polycyclic aliphatic group which has between 5 and 24, preferably
between 5 and 16, more preferably between 5 and 14, even more
preferably between 5 and 12, yet more preferably 5 or 6 carbon
atoms, with one or more double carbon-carbon bonds, preferably 1, 2
or 3 double carbon-carbon bonds, conjugated or unconjugated, bound
to the rest of the molecule by a simple bond, including, for
example and not restricted to, the cyclopent-1-en-1-yl group and
similar.
[0028] The term "cycloalkynyl" refers to a non-aromatic mono- or
polycyclic aliphatic group which has between 8 and 24, preferably
between 8 and 16, more preferably between 8 and 14, even more
preferably between 8 and 12, yet more preferably 8 or 9 carbon
atoms, with one or more triple carbon-carbon bonds, preferably 1, 2
or 3 triple carbon-carbon bonds, conjugated or unconjugated, bound
to the rest of the molecule by a simple bond, including, for
example and not restricted to, the cyclooct-2-in-1-yl group and
similar. The cycloalkynyl groups can also contain one or more
double carbon-carbon bonds, including for example and not
restricted to, the cyclooct-4-en-2-ynyl group and similar.
[0029] The term "aryl group" refers to an aromatic group which has
between 6 and 30, preferably between 6 and 18, more preferably
between 6 and 10, even more preferably between 6 or 10 carbon
atoms, which comprises 1, 2, 3 or 4 aromatic rings, bound by a
carbon-carbon bond or condensed, including, for example and not
restricted to, phenyl, naphthyl, diphenyl, indenyl, phenanthryl or
anthranyl, among others; or an aralkyl group.
[0030] The term "aralkyl group" refers to an alkyl group
substituted by an aromatic group, with between 7 and 24 carbon
atoms and including, for example and not restricted to,
--(CH.sub.2).sub.1-6-phenyl, --(CH.sub.2).sub.1-6-(1-naphthyl),
--(CH.sub.2).sub.1-6-(2-naphthyl),
--(CH.sub.2).sub.1-6--CH(phenyl).sub.2 and similar.
[0031] The term "heterocyclyl group" refers to a hydrocarbonated
ring of 3-10 members, in which one or more of the atoms in the
ring, preferably 1, 2 or 3 of the atoms in the ring, is a different
element to carbon, such as nitrogen, oxygen or sulfur and can be
saturated or unsaturated. For the purposes of this invention, the
heterocycle can be a monocyclic, bicyclic or tricyclic system,
which can include systems of condensed rings; and the nitrogen,
carbon or sulfur atoms can optionally be oxidized in the radical
heterocycle; the nitrogen atom can optionally be quaternized; and
the radical heterocyclyl can be partially or completely saturated
or aromatic. The greatest preference is for the term heterocyclyl
to refer to a ring of 5 or 6 members. Examples of saturated
heterocyclic groups are dioxane, piperidine, piperazine,
pyrrolidine, morpholine and thiomorpholine. Examples of aromatic
heterocyclic groups, also known as heteroaromatic groups are
pyridine, pyrrol, furan, thiophene, benzofuran, imidazoline,
quinolein, quinoline, pyridazine and naphthyridine.
[0032] The term "heteroarylalkyl group" refers to an alkyl group
substituted by a substituted or unsubstituted aromatic heterocyclyl
group, the alkyl group having from 1 to 6 carbon atoms and the
aromatic heterocyclyl group between 2 and 24 carbon atoms and from
1 to 3 atoms other than carbon and including, for example and not
restricted to, --(CH.sub.2).sub.1-6-imidazolyl,
--(CH.sub.2).sub.1-6-triazol, --(CH.sub.2).sub.1-6-thienyl,
--(CH.sub.2).sub.1-6-furyl, --(CH.sub.2).sub.1-6-pyrrolidinyl and
similar.
[0033] As is understood in this technical field, there can be a
certain level of substitution of the aforementioned groups.
Therefore, there can be substitution in any of the groups of this
invention where specifically stated. The references in this
document to substituted groups in the groups of this invention
indicate that the specified radical can be substituted in one or
more positions available by one or more substituents, preferably in
1, 2 or 3 positions, more preferably in 1 or 2 positions, yet more
preferably in 1 position. These substituents include, alkyl
C.sub.1-C.sub.4; hydroxyl; alcoxyl C.sub.1-C.sub.4; amino;
aminoalkyl carbonyloxyl C.sub.1-C.sub.4; oxycarbonyl
C.sub.1-C.sub.4; halogen such as fluoride, chlorine, bromine and
iodine; cyano; nitro; azide; alkylsulfonyl C.sub.1-C.sub.4; thiol;
alkylthio C.sub.1-C.sub.4; aryloxyl such as phenoxyl;
--NR.sub.b(C.dbd.NR.sub.b)NR.sub.bR.sub.c; wherein R.sub.b and
R.sub.c are independently selected from the group formed by H,
alkyl C.sub.1-C.sub.4, alkenyl C.sub.2-C.sub.4, alkynyl
C.sub.2-C.sub.4, cycloalkyl C.sub.3-C.sub.10, aryl
C.sub.6-C.sub.18, aralkyl C.sub.7-C.sub.17, heterocyclyl of 3-10
members or protective group of the amino group.
Compounds in the Invention
[0034] A first aspect of the invention refers to a compound of
general formula (I):
R.sub.1--W.sub.n--X.sub.m-AA.sub.1-AA.sub.2-AA.sub.3-AA.sub.4-AA.sub.5-A-
A.sub.6-AA.sub.7-Y.sub.p--Z.sub.q--R.sub.2 (I)
its stereoisomers, mixtures thereof and/or its cosmetically or
pharmaceutically acceptable salts, characterized in that: [0035]
AA.sub.1 is selected from the group formed by -Arg-, -His-, -Lys-,
-Gln-, -Asn-, -Glu- and -Asp-; [0036] AA.sub.2 is selected from the
group formed by -His-, -Gln-, -Asn-, -Glu- and -Asp-; [0037]
AA.sub.3 is selected from the group formed by -Leu-, -Ile-, -Phe-
and -Tyr-; [0038] AA.sub.4 is selected from the group formed by
-Lys-, -His-, -Arg-, -Gln-, -Leu-, -Ile-, -Met-, -MetO-- and
-MetO.sub.2--; [0039] AA.sub.5 is selected from the group formed by
-Arg-, -His-, -Lys-, -Gln-, -Asn-, -Glu- and -Asp-; [0040] AA.sub.6
is selected from the group formed by -Phe-, -Trp-, -Ile- and -Val-;
[0041] AA.sub.7 is selected from the group formed by -Met-, -MetO--
and -MetO.sub.2--; [0042] W, X, Y, Z are amino acids and are
independently selected from amongst themselves; [0043] n, m, p and
q are independently selected from amongst themselves and have a
value of 0 or 1; [0044] n+m+p+q is smaller or equal to 2; [0045]
with the condition that it is not
Trp-Lys-Lys-His-Leu-Leu-Lys-Ile-Met (SEQ ID NO:111); [0046] R.sub.1
is selected from the group formed by H, a polymer derived from
polyethylene glycol, a non-cyclic substituted or unsubstituted
aliphatic group, substituted or unsubstituted alicyclyl,
substituted or unsubstituted heterocyclyl, substituted or
unsubstituted heteroarylalkyl, substituted or unsubstituted aryl,
substituted or unsubstituted aralkyl and R.sub.5--CO--, wherein
R.sub.5 is selected from the group formed by H, a non-cyclic
substituted or unsubstituted aliphatic group, substituted or
unsubstituted alicyclyl, substituted or unsubstituted aryl,
substituted or unsubstituted aralkyl, substituted or unsubstituted
heterocyclyl and substituted or unsubstituted heteroarylalkyl;
[0047] R.sub.2 is selected from the group formed by
--NR.sub.3R.sub.4, --OR.sub.3 and --SR.sub.3, wherein R.sub.3 and
R.sub.4 are independently selected from the group formed by H, a
polymer derived from polyethylene glycol, a non-cyclic substituted
or unsubstituted aliphatic group, substituted or unsubstituted
alicyclyl, substituted or unsubstituted heterocyclyl, substituted
or unsubstituted heteroarylalkyl, substituted or unsubstituted
aryl, and substituted or unsubstituted aralkyl; and [0048] R.sub.1
and R.sub.2 are not .alpha.-amino acids.
[0049] Groups R.sub.1 and R.sub.2 are bound to the amino-terminal
(N-terminal) and carboxy-terminal (C-terminal) ends of the peptide
sequences respectively.
[0050] In accordance with a preferred embodiment of this invention
R.sub.1 is selected from the group formed by H, a polymer derived
from polyethylene glycol and R.sub.5--CO--, wherein R.sub.5 is
selected from the group formed by substituted or unsubstituted
alkyl radical C.sub.1-C.sub.24, substituted or unsubstituted
alkenyl C.sub.2-C.sub.24, substituted or unsubstituted alkynyl
C.sub.2-C.sub.24, substituted or unsubstituted cycloalkyl
C.sub.3-C.sub.24, substituted or unsubstituted cycloalkenyl
C.sub.5-C.sub.24, substituted or unsubstituted cycloalkynyl
C.sub.8-C.sub.24, substituted or unsubstituted aryl
C.sub.6-C.sub.30, substituted or unsubstituted aralkyl
C.sub.7-C.sub.24, substituted or unsubstituted heterocyclyl ring of
3-10 members, and substituted or unsubstituted heteroarylalkyl of 2
to 24 carbon atoms and 1 to 3 atoms other than carbon and an alkyl
chain of 1 to 6 carbon atoms and R.sub.5--CO-- is not an
.alpha.-amino acid. More preferably, R.sub.1 is selected from the
group formed by H, a polymer derived from polyethylene glycol with
a molecular weight comprised between 200 and 35000 Daltons, acetyl,
tert-butanoyl, prenyl, hexanoyl, 2-methylhexanoyl,
cyclohexanecarboxyl, octanoyl, decanoyl, lauroyl, myristoyl,
palmitoyl, stearoyl, oleoyl and linoleoyl. Even more preferably,
R.sub.1 is H, acetyl, lauroyl, myristoyl or palmitoyl. In an even
more preferred embodiment, R.sub.1 is acetyl or palmitoyl.
[0051] In accordance with another preferred embodiment, R.sub.2 is
selected from the group formed by --NR.sub.3R.sub.4, --OR.sub.3,
--SR.sub.3, wherein R.sub.3 and R.sub.4 are independently selected
from the group formed by H, a polymer derived from polyethylene
glycol, substituted or unsubstituted alkyl C.sub.1-C.sub.24,
substituted or unsubstituted alkenyl C.sub.2-C.sub.24, substituted
or unsubstituted alkynyl C.sub.2-C.sub.24, substituted or
unsubstituted cycloalkyl C.sub.3-C.sub.24, substituted or
unsubstituted cycloalkenyl C.sub.5-C.sub.24, substituted or
unsubstituted cycloalkynyl C.sub.8-C.sub.24, substituted or
unsubstituted aryl C.sub.6-C.sub.30, substituted or unsubstituted
aralkyl C.sub.7-C.sub.24, substituted or unsubstituted heterocyclyl
ring of 3-10 members, and substituted or unsubstituted
heteroarylalkyl of 2 to 24 carbon atoms and 1 to 3 atoms other than
carbon wherein the alkyl chain is of 1 to 6 carbon atoms and
--NR.sub.3R.sub.4 is not an .alpha.-amino acid. Optionally, R.sub.3
and R.sub.4 can be bound by a saturated or unsaturated
carbon-carbon bond, forming a cycle with the nitrogen atom. More
preferably R.sub.2 is --NR.sub.3R.sub.4 or --OR.sub.3. More
preferably, R.sub.3 and R.sub.4 are independently selected from the
group formed by H, a polymer derived from polyethylene glycol with
a molecular weight comprised between 200 and 35000 Daltons, methyl,
ethyl, hexyl, dodecyl, or hexadecyl. Even more preferably R.sub.3
and R.sub.4 are independently selected from the group formed by H,
methyl, ethyl, hexyl, dodecyl, or hexadecyl. Even more preferably
R.sub.3 is H and R.sub.4 is selected from the group formed by H,
methyl, ethyl, hexyl, dodecyl, and hexadecyl. In accordance with an
even more preferred embodiment, R.sub.2 is selected from --OH and
--NH.sub.2.
[0052] In accordance with another embodiment of this invention
R.sub.1 is selected from the group formed by H, acetyl, lauroyl,
myristoyl or palmitoyl, preferably R.sub.1 is selected from the
group formed by H, acetyl and palmitoyl and R.sub.2 is selected
from the group formed by --OH and --NH.sub.2.
[0053] In accordance with another particular embodiment the most
preferred structures of the polymer derived from polyethylene
glycol are the group (--CH.sub.2--CH.sub.2--O).sub.r--H in which r
is a number between 4 and 795 and the group
##STR00020##
where s is a number between 1 and 125.
[0054] In accordance with another embodiment of this invention n,
m, p and q are 0.
[0055] In accordance with another embodiment of this invention
AA.sub.1 is selected from the group formed by -Arg-, -Lys-, -Gln-,
-Asn-, -Glu- and -Asp-, AA.sub.2 is selected from the group formed
by -His-, -Gln-, -Asn-, -Glu- and -Asp-, AA.sub.3 is selected from
the group formed by -Leu- and -Phe-, AA.sub.4 is selected from the
group formed by -His-, -Lys-, -Gln- and -Leu-, AA.sub.5 is selected
from the group formed by -Arg-, -His-, -Lys-, -Gln-, -Asn-, -Glu-
and -Asp-, AA.sub.6 is selected from the group formed by -Trp- and
-Val- and AA.sub.7 is selected from the group formed by -Met-,
-MetO-- and -MetO.sub.2. More preferably, AA.sub.4 is selected from
the group formed by -Lys- and -Leu-, and AA.sub.6 is -Trp-. Even
more preferably, n, m, p and q are 0. Additionally, the inventors
of the present invention have found that when AA.sub.2 is selected
from the group formed by -Asn- and -Glu-, the obtained compound is
more chemically stable compared with other amino acids in
AA.sub.2.
[0056] In accordance with another embodiment of this invention
R.sub.1 is selected from the group formed by H, acetyl, lauroyl,
myristoyl and palmitoyl, AA.sub.1 is selected from the group formed
by -L-Arg-, -L-Lys-, -L-Gln-, -L-Asn-, -L-Glu- and -L-Asp-,
AA.sub.2 is selected from the group formed by -L-His-, -L-Gln-,
-L-Asn-, -L-Glu- and -L-Asp-, AA.sub.3 is selected from the group
formed by -L-Leu- and -L-Phe-, AA.sub.4 is selected from the group
formed by -L-His-, -L-Lys-, -L-Gln- and -L-Leu-, AA.sub.5 is
selected from the group formed by -L-Arg-, -L-His-, -L-Lys-,
-L-Gln-, -L-Asn-, -L-Glu- and -L-Asp-, AA.sub.6 is selected from
the group formed by -L-Trp- and -L-Val-, AA.sub.7 is selected from
the group formed by -L-Met-, -L-MetO-- and -L-MetO.sub.2--, and
R.sub.2 is selected from the group formed by --NR.sub.3R.sub.4 and
--OR.sub.3 where R.sub.3 and R.sub.4 are independently selected
from H, methyl, ethyl, hexyl, dodecyl and hexadecyl. More
preferably, AA.sub.4 is selected from the group formed by -L-Lys-
and -L-Leu-, and AA.sub.6 is -L-Trp-. More preferably, R.sub.1 is
acetyl or palmitoyl and R.sub.2 is --NH.sub.2. Even more
preferably, n, m, p and q are 0.
[0057] In accordance with another embodiment of this invention
R.sub.1 is selected from the group formed by H, acetyl, lauroyl,
myristoyl and palmitoyl, AA.sub.1 is selected from the group formed
by -L-Asn-, -L-Glu- and -L-Asp-, AA.sub.2 is selected from the
group formed by -L-His- and -L-Asp-, AA.sub.3 is selected from the
group formed by -L-Leu- and -L-Phe-, AA.sub.4 is selected from the
group formed by -L-Lys-, -L-Gln- and -L-Leu-, AA.sub.5 is selected
from the group formed by -L-Arg-, -L-Gln-, -L-Asn- and -L-Asp-,
AA.sub.6 is selected from the group formed by -L-Trp-, AA.sub.7 is
selected from the group formed by -L-Met-, -L-MetO-- and
-L-MetO.sub.2--, and R.sub.2 is selected from the group formed by
--NR.sub.3R.sub.4 and --OR.sub.3 where R.sub.3 and R.sub.4 are
independently selected from H, methyl, ethyl, hexyl, dodecyl and
hexadecyl. More preferably, R.sub.1 is acetyl or palmitoyl and
R.sub.2 is --NH.sub.2. Even more preferably, n, m, p and q are
0.
[0058] In accordance with another embodiment of this invention
R.sub.1 is selected from the group formed by H, acetyl, lauroyl,
myristoyl and palmitoyl, AA.sub.1 is -L-Glu-, AA.sub.2 is selected
from the group formed by -L-Asn-, -L-Glu-, -L-Gln- and -L-Asp-,
AA.sub.3 is -L-Leu-, AA.sub.4 is -L-Lys-, AA.sub.5 is -L-Arg-,
AA.sub.6 is -L-Trp-, AA.sub.7 is selected from the group formed by
-L-Met-, -L-MetO-- and -L-MetO.sub.2--, and R.sub.2 is selected
from the group formed by --NR.sub.3R.sub.4 and --OR.sub.3 where
R.sub.3 and R.sub.4 are independently selected from H, methyl,
ethyl, hexyl, dodecyl and hexadecyl. More preferably, R.sub.1 is
acetyl or palmitoyl and R.sub.2 is --NH.sub.2. Even more
preferably, n, m, p and q are 0.
[0059] In accordance with another embodiment of this invention
R.sub.1 is selected from the group formed by H, acetyl, lauroyl,
myristoyl or palmitoyl, AA.sub.1 is -L-Glu-, AA.sub.2 is -L-His-,
AA.sub.3 is -L-Leu-, AA.sub.4 is -L-Lys-, AA.sub.5 is -L-Gln-,
AA.sub.6 is -L-Trp-, AA.sub.7 is -L-Met-, -L-MetO-- or
-L-MetO.sub.2-- and R.sub.2 is --NR.sub.3R.sub.4 or --OR.sub.3
where R.sub.3 and R.sub.4 are independently selected from H,
methyl, ethyl, hexyl, dodecyl and hexadecyl, preferably R.sub.2 is
--OH or --NH.sub.2. More preferably, R.sub.1 is acetyl or palmitoyl
and R.sub.2 is --NH.sub.2. Even more preferably, n, m, p and q are
0.
[0060] In accordance with another embodiment of this invention
R.sub.1 is selected from the group formed by H, acetyl, lauroyl,
myristoyl or palmitoyl, AA.sub.1 is -L-Glu-, AA.sub.2 is -L-Asp-,
AA.sub.3 is -L-Leu-, AA.sub.4 is -L-Lys-, AA.sub.5 is -L-Arg-,
AA.sub.6 is -L-Trp-, AA.sub.7 is -L-Met-, -L-MetO-- or
-L-MetO.sub.2-- and R.sub.2 is --NR.sub.3R.sub.4 or --OR.sub.3
where R.sub.3 and R.sub.4 are independently selected from H,
methyl, ethyl, hexyl, dodecyl and hexadecyl, preferably R.sub.2 is
--OH or --NH.sub.2. More preferably, R.sub.1 is acetyl or palmitoyl
and R.sub.2 is --NH.sub.2. Even more preferably, n, m, p and q are
0.
[0061] In accordance with another embodiment of this invention
R.sub.1 is selected from the group formed by H, acetyl, lauroyl,
myristoyl or palmitoyl, AA.sub.1 is -L-Asn-, AA.sub.2 is -L-His-,
AA.sub.3 is -L-Phe-, AA.sub.4 is -L-Leu-, AA.sub.5 is -L-Asn-,
AA.sub.6 is -L-Trp-, AA.sub.7 is -L-Met-, -L-MetO-- or
-L-MetO.sub.2-- and R.sub.2 is --NR.sub.3R.sub.4 or --OR.sub.3
where R.sub.3 and R.sub.4 are independently selected from H,
methyl, ethyl, hexyl, dodecyl and hexadecyl, preferably R.sub.2 is
--OH or --NH.sub.2. More preferably, R.sub.1 is acetyl or palmitoyl
and R.sub.2 is --NH.sub.2. Even more preferably, n, m, p and q are
0.
[0062] In accordance with another embodiment of this invention
R.sub.1 is selected from the group formed by H, acetyl, lauroyl,
myristoyl or palmitoyl, AA.sub.1 is -L-Asp-, AA.sub.2 is -L-His-,
AA.sub.3 is -L-Phe-, AA.sub.4 is -L-Leu-, AA.sub.5 is -L-Asp-,
AA.sub.6 is -L-Trp-, AA.sub.7 is -L-Met-, -L-MetO-- or
-L-MetO.sub.2-- and R.sub.2 is --NR.sub.3R.sub.4 or --OR.sub.3
where R.sub.3 and R.sub.4 are independently selected from H,
methyl, ethyl, hexyl, dodecyl and hexadecyl, preferably R.sub.2 is
--OH or --NH.sub.2. More preferably, R.sub.1 is acetyl or palmitoyl
and R.sub.2 is --NH.sub.2. Even more preferably, n, m, p and q are
0.
[0063] In particular, the compounds in the invention which inhibit
neuronal exocytosis, represented according to the formula (I) are
selected from the group of peptide sequences outlined in Table 2,
in which their sequence identifier is detailed:
TABLE-US-00002 TABLE 2 SEQUENCE IDENTIFIER EHLKQWM SEQ ID NO: 1
QDFLHWM SEQ ID NO: 2 QHLHNVM SEQ ID NO: 3 KDIKNWM SEQ ID NO: 4
DHLKQFM SEQ ID NO: 5 EHMKQYM SEQ ID NO: 6 KDLKEWM SEQ ID NO: 7
EHLKKWM SEQ ID NO: 8 DHLKEWM SEQ ID NO: 9 KDLRRWM SEQ ID NO: 10
DDLKRYM SEQ ID NO: 11 QHLKEWM SEQ ID NO: 12 RHFLQWM SEQ ID NO: 13
EDLKRWM SEQ ID NO: 14 NHFLNWM SEQ ID NO: 15 RHLKDWM SEQ ID NO: 16
DHFNQRM SEQ ID NO: 17 EDFQQHM SEQ ID NO: 18 EHFLEFM SEQ ID NO: 19
KHLQQIM SEQ ID NO: 20 NHFLKWM SEQ ID NO: 21 DHLKKWM SEQ ID NO: 22
NDLKDWM SEQ ID NO: 23 DHFQQRM SEQ ID NO: 24 DHFLDWM SEQ ID NO: 25
DHFLQWM SEQ ID NO: 26 QHLKNWM SEQ ID NO: 27 RDLIRKM SEQ ID NO: 28
NHFNNKM SEQ ID NO: 29 EHFLQWM SEQ ID NO: 30 NHLKNWM SEQ ID NO: 31
NHLKHWM SEQ ID NO: 32 QHFLRWM SEQ ID NO: 33 DHFLNWM SEQ ID NO: 34
EHLRQWM SEQ ID NO: 35 EHIKQWM SEQ ID NO: 36 EHMRQVM SEQ ID NO: 37
EHIMHWM SEQ ID NO: 38 DHMNRVM SEQ ID NO: 39 DDMKRWM SEQ ID NO: 40
NHYLNWM SEQ ID NO: 41 QHFINRM SEQ ID NO: 42 NHFVNYM SEQ ID NO: 43
QHFLNFM SEQ ID NO: 44 EHYQQRM SEQ ID NO: 45 RHLVQMM SEQ ID NO: 46
HHLIQMM SEQ ID NO: 47 HDIVRHM SEQ ID NO: 48 KHMMQIM SEQ ID NO: 49
Glu-His-Leu-Lys-Gln- SEQ ID NO: 50 Trp-MetO Gln-Asp-Phe-Leu-His-
SEQ ID NO: 51 Trp-MetO Gln-His-Leu-His-Asn- SEQ ID NO: 52 Val-MetO
Glu-Asp-Leu-Lys-Arg- SEQ ID NO: 53 Trp-MetO Asn-His-Phe-Leu-Asn-
SEQ ID NO: 54 Trp-MetO Asp-His-Phe-Gln-Gln- SEQ ID NO: 55 Arg-MetO
Asp-His-Phe-Leu-Asp- SEQ ID NO: 56 Trp-MetO Asp-His-Phe-Leu-Asn-
SEQ ID NO: 57 Trp-MetO Glu-His-Leu-Lys-Gln- SEQ ID NO: 58
Trp-MetO.sub.2 Glu-Asp-Leu-Lys-Arg- SEQ ID NO: 59 Trp-MetO.sub.2
Asp-His-Phe-Gln-Gln- SEQ ID NO: 60 Arg-MetO.sub.2
Asp-His-Phe-Leu-Asp- SEQ ID NO: 61 Trp-MetO.sub.2 EEHLKQWM SEQ ID
NO: 62 EHLKQWMR SEQ ID NO: 63 RQDFLHWM SEQ ID NO: 64 QDFLHWMH SEQ
ID NO: 65 DQHLHNVM SEQ ID NO: 66 QHLHNVMK SEQ ID NO: 67 EQHLKEWM
SEQ ID NO: 68 QHLKEWMR SEQ ID NO: 69 DEDLKRWM SEQ ID NO: 70
EDLKRWMK SEQ ID NO: 71 ENHFLNWM SEQ ID NO: 72 NHFLNWMH SEQ ID NO:
73 DDHLKKWM SEQ ID NO: 74 DHLKKWMR SEQ ID NO: 75 DDHFQQRM SEQ ID
NO: 76 DHFQQRMR SEQ ID NO: 77 EDHFLDWM SEQ ID NO: 78 DHFLDWMK SEQ
ID NO: 79 ENHLKNWM SEQ ID NO: 80 NHLKNWMH SEQ ID NO: 81 DDHFLNWM
SEQ ID NO: 82 DHFLNWMR SEQ ID NO: 83 Glu-His-Leu-Lys-Gln-Trp- SEQ
ID NO: 84 MetO-Arg Asp-Glu-Asp-Leu-Lys-Arg- SEQ ID NO: 85 Trp-MetO
Asn-His-Phe-Leu-Asn-Trp- SEQ ID NO: 86 MetO-Arg
Asp-His-Phe-Gln-Gln-Arg- SEQ ID NO: 87 MetO-Arg
Asp-His-Phe-Leu-Asp-Trp- SEQ ID NO: 88 MetO-Lys
Glu-His-Leu-Lys-Gln-Trp- SEQ ID NO: 89 MetO.sub.2-Arg
Asp-Glu-Asp-Leu-Lys-Arg- SEQ ID NO: 90 Trp-MetO.sub.2
Asp-His-Phe-Gln-Gln-Arg- SEQ ID NO: 91 MetO.sub.2-Arg
Asp-His-Phe-Leu-Asp-Trp- SEQ ID NO: 92 MetO.sub.2-Lys EEHLKQWMR SEQ
ID NO: 93 EHLKQWMRR SEQ ID NO: 94 DEQHLHNVM SEQ ID NO: 95 QHLHNVMRR
SEQ ID NO: 96 EEDLKRWMM SEQ ID NO: 97 DEEDLKRWM SEQ ID NO: 98
QRNHFLNWM SEQ ID NO: 99 NHFLNWMMR SEQ ID NO: 100 EDHFQQRML SEQ ID
NO: 101 DDHFQQRMR SEQ ID NO: 102 DHFLDWMRR SEQ ID NO: 103 DHDHFLDWM
SEQ ID NO: 104 EHFLQWMRM SEQ ID NO: 105 DEHFLQWMV SEQ ID NO: 106
Glu-His-Leu-Lys-Gln-Trp-MetO- SEQ ID NO: 107 Arg-Lys
Gln-Arg-Asn-His-Phe-Leu-Asn- SEQ ID NO: 108 Trp-MetO
Glu-His-Leu-Lys-Gln-Trp-MetO.sub.2- SEQ ID NO: 109 Arg-Lys
Gln-Arg-Asn-His-Phe-Leu-Asn- SEQ ID NO: 110 Trp-MetO.sub.2 EDVKRWM
SEQ ID NO: 112
EQLKRWM SEQ ID NO: 113 DDVKKFM SEQ ID NO: 114 DNLKRFM SEQ ID NO:
115 EELKRWM SEQ ID NO: 116 ENLKRWM SEQ ID NO: 117 EDVRRWM SEQ ID
NO: 118 EHFLEWM SEQ ID NO: 119 DEIHKWM SEQ ID NO: 120 ENLRRWM SEQ
ID NO: 121 DNLHKYM SEQ ID NO: 122 EQIKHFM SEQ ID NO: 123 DNMRRFM
SEQ ID NO: 124 EEMKRWM SEQ ID NO: 125 DQMKHYM SEQ ID NO: 126
Glu-Glu-Leu-Lys-Arg-Trp-MetO SEQ ID NO: 127
Asp-Asp-Val-His-Arg-Trp-MetO SEQ ID NO: 128
Glu-Asn-Leu-Lys-Arg-Trp-MetO SEQ ID NO: 129
Asp-Glu-Val-Arg-His-Tyr-MetO SEQ ID NO: 130
Glu-Glu-Leu-Lys-Arg-Trp-MetO.sub.2 SEQ ID NO: 131
Glu-Asn-Leu-Lys-Arg-Trp-MetO.sub.2 SEQ ID NO: 132
Asp-Gln-Ile-Arg-Lys-Phe-MetO.sub.2 SEQ ID NO: 133 EEQLKRWM SEQ ID
NO: 134 EQLKRWMR SEQ ID NO: 135 REELKRWM SEQ ID NO: 136 EELKRWMH
SEQ ID NO: 137 DENLKRWM SEQ ID NO: 138 ENLKRWMK SEQ ID NO: 139
EDNLKRFM SEQ ID NO: 140 DNLKRFMR SEQ ID NO: 141 EEQIKHFM SEQ ID NO:
142 EQIKHFMH SEQ ID NO: 143 Glu-Glu-Leu-Lys-Arg-Trp-MetO-Arg SEQ ID
NO: 144 Glu-Asn-Leu-Lys-Arg-Trp-MetO-Arg SEQ ID NO: 145
Glu-Glu-Leu-Lys-Arg-Trp-MetO.sub.2-Arg SEQ ID NO: 146
Glu-Asn-Leu-Lys-Arg-Trp-MetO.sub.2-Arg SEQ ID NO: 147 EEQLKRWMR SEQ
ID NO: 148 EQLKRWMRR SEQ ID NO: 149 DEELKRWMR SEQ ID NO: 150
EELKRWMRR SEQ ID NO: 151 QRENLKRWM SEQ ID NO: 152 ENLKRWMMR SEQ ID
NO: 153 QREQIKHFM SEQ ID NO: 154 EQIKHFMMR SEQ ID NO: 155
Glu-Glu-Leu-Lys-Arg-Trp-MetO- SEQ ID NO: 156 Arg-Lys
Gln-Arg-Glu-Asn-Leu-Lys-Arg- SEQ ID NO: 157 Trp-MetO
Glu-Asn-Leu-Lys-Arg-Trp-MetO.sub.2- SEQ ID NO: 158 Arg-Lys
Gln-Arg-Glu-Glu-Leu-Lys-Arg- SEQ ID NO: 159 Trp-MetO.sub.2
[0064] their stereoisomers, mixtures thereof and/or their
cosmetically or pharmaceutically acceptable salts.
[0065] The compounds of this invention can exist as stereoisomers
or mixtures of stereoisomers; for example, the amino acids which
comprise them can have the configuration L-, D-, or be racemic
independently of each other. Therefore, it is possible to obtain
isomeric mixtures as well as racemic mixtures or diastereomeric
mixtures, or pure diastereomers or enantiomers, depending on the
number of asymmetric carbons and on which isomers or isomeric
mixtures are present. The preferred structures of the compounds of
the invention are pure isomers, i.e., enantiomers or
diastereomers.
[0066] For example, when it is stated that AA.sub.1 can be -Lys-,
it is understood that AA.sub.1 is selected from -L-Lys-, -D-Lys- or
mixtures of both, racemic or non-racemic. The preparation
procedures described in this document enable the person skilled in
the art to obtain each of the stereoisomers of the compound of the
invention by choosing the amino acid with the right
configuration.
[0067] In the context of this invention, the term "amino acids"
includes the amino acids encoded by the genetic code as well as
non-encoded amino acids, whether they are natural or not. Examples
of non-encoded amino acids are, without restriction, citrulline,
ornithine, sarcosine, desmosine, norvaline, 4-aminobutyric acid,
2-aminobutyric acid, 2-aminoisobutyric acid, 6-aminohexanoic acid,
1-naphthylalanine, 2-naphthylalanine, 2-aminobenzoic acid,
4-aminobenzoic acid, 4-chlorophenylalanine, 2,3-diaminopropionic
acid, 2,4 diaminobutyric acid, cycloserine, carnitine, cystine,
penicillamine, pyroglutamic acid, thienylalanine, hydroxyproline,
allo-isoleucine, allo-threonine, isonipecotic acid, isoserine,
phenylglycine, statin, .beta.-alanine, norleucine, N-methyl amino
acids, .alpha.-amino acids and .beta.-amino acids, among others, as
well as their derivatives. A list of non-natural amino acids can be
found in the article "Unusual amino acids in peptide synthesis" by
D. C. Roberts and F. Vellaccio, in The Peptides, Vol. 5 (1983),
Chapter VI, Gross E. and Meienhofer J., Eds., Academic Press, New
York, USA or in the commercial catalogs of the companies
specialized in the field.
[0068] In the context of this invention, when n, m, p or q are not
0 it is clearly understood that the nature of W, X, Y and/or Z does
not hinder the activity of the compounds of the invention, but that
it contributes to the inhibition of neuronal exocytosis or has no
effect on it.
[0069] The cosmetically and pharmaceutically acceptable salts of
the peptides provided by this invention are also found within the
field of this invention. The term "cosmetically or pharmaceutically
acceptable salts" means a salt recognized for its use in animals
and more specifically in human beings, and includes salts used to
form base addition salts, either they are inorganic, such as and
not restricted to, lithium, sodium, potassium, calcium, magnesium,
manganese, copper, zinc or aluminum among others, either they are
organic, such as and not restricted to, ethylamine, diethylamine,
ethylenediamine, ethanolamine, diethanolamine, arginine, lysine,
histidine or piperazine among others, or acid addition salts,
either they are organic, such as and not restricted to, acetate,
citrate, lactate, malonate, maleate, tartrate, fumarate, benzoate,
aspartate, glutamate, succinate, oleate, trifluoroacetate, oxalate,
pamoate or gluconate among others, or inorganic, such as and not
restricted to, chloride, sulfate, borate or carbonate, among
others. The nature of the salt is not critical, provided that it is
cosmetically or pharmaceutically acceptable. The cosmetically or
pharmaceutically acceptable salts of the peptides of the invention
can be obtained by the conventional methods, well known in the
prior art [Berge S. M. et al., "Pharmaceutical Salts", (1977), J.
Pharm. Sci., 66, 119].
Preparation Procedures of the Compounds of the Invention
[0070] Synthesis of the compounds of the invention, their
stereoisomers, mixtures thereof and/or their cosmetically or
pharmaceutically acceptable salts can be carried out according to
conventional methods, known in the prior art, such as using solid
phase peptide synthesis methods [Stewart J. M. and Young J. D.,
"Solid Phase Peptide Synthesis, 2nd edition", (1984), Pierce
Chemical Company, Rockford, Ill.; Bodanzsky M. and Bodanzsky A.,
"The practice of Peptide Synthesis", (1994), Springer Verlag,
Berlin; Lloyd-Williams P. et al., "Chemical Approaches to the
Synthesis of Peptides and Proteins", (1997), CRC, Boca Raton, Fla.,
USA], synthesis in solution, enzymatic synthesis [Kullmann W
"Proteases as catalysts for enzymic syntheses of opioid peptides",
(1980), J. Biol. Chem., 255(17), 82348238] or any combination
thereof. Compounds can also be obtained by fermentation of a strain
of bacteria, modified or unmodified, by genetic engineering with
the objective of producing the desired sequences, or by controlled
hydrolysis of proteins with animal, fungal, or preferably plant
origins, which free peptide fragments which contain, at least, the
desired sequence.
[0071] For example, a method of obtaining the compounds (I) of the
invention, their stereoisomers and mixtures thereof comprises the
stages of: [0072] coupling of an amino acid, with the N-terminal
end protected and the C-terminal end free, with an amino acid with
the N-terminal end free and the C-terminal end protected or bound
to a solid support; [0073] elimination of the group protecting the
N-terminal end; [0074] repetition of the coupling sequence and
elimination of the group protecting the N-terminal end until the
desired peptide sequence is obtained; [0075] elimination of the
group protecting the C-terminal end or cleavage of the solid
support.
[0076] Preferably, the C-terminal end is bound to a solid support
and the procedure is carried out in solid phase and, therefore,
comprises the coupling of an amino acid with the protected
N-terminal end and the free C-terminal end with an amino acid with
the N-terminal end free and the C-terminal end bound to a polymeric
support; elimination of the group protecting the N-terminal end;
and repetition of this sequence as many times as is necessary to
thus obtain the compound of the desired length, finally followed by
the cleavage of the synthesized compound from the original
polymeric support.
[0077] The functional groups of the side chains of the amino acids
are maintained conveniently protected with temporary or permanent
protective groups throughout synthesis, and can be unprotected
simultaneously or orthogonally to the process of cleavage of the
peptide from the polymeric support.
[0078] Alternatively, solid phase synthesis can be carried out
using a convergent strategy coupling a peptide with the polymeric
support or with a peptide or amino acid previously bound to the
polymeric support. Convergent synthesis strategies are widely known
by persons skilled in the art and are described in Lloyd-Williams
P. et al., "Convergent Solid-Phase Peptide Synthesis", (1993),
Tetrahedron, 49(48), 11065-11133.
[0079] The procedure can comprise the additional stages of
deprotection of the N-terminal and C-terminal ends and/or cleavage
of the peptide from the polymeric support in an indiscriminate
order, using standard procedures and conditions known in the prior
art, after which the functional groups of these ends can be
modified. The optional modification of the N-terminal and
C-terminal ends can be carried out with the peptide of formula (I)
anchored to the polymeric support or once the peptide has been
separated from the polymeric support.
[0080] Optionally, R.sub.1 can be introduced by the reaction of the
N-terminal end of the compound of the invention with a R.sub.1--X
compound, wherein R.sub.1 has the aforementioned meaning and X is a
leaving group, such as and not restricted to, the tosyl group, the
mesyl group and halogen groups among others; through a nucleophilic
substitution reaction, in the presence of an adequate base and
solvent, wherein the fragments that have the functional groups not
involved in the N--C bond formation are suitably protected with
temporary or permanent protective groups.
[0081] Optionally and/or additionally, the R.sub.2 radicals can be
introduced by the reaction of a compound HR.sub.2 wherein R.sub.2
is --OR.sub.3, --NR.sub.3R.sub.4 or --SR.sub.3, with a
complementary fragment which corresponds to the compound of formula
(I) in which R.sub.2 is --OH in the presence of an adequate solvent
and a base such as, N,N-diisopropylethylamine (DIEA) or
triethylamine or an additive such as 1-hydroxybenzotriazole (HOBt)
or 1-hydroxyazabenzotriazole (HOAt) and a dehydrating agent, such
as a carbodiimide, a uronium salt, a phosphonium salt or amidinium
salt, among others, or by prior formation of an acyl halide with,
for example, thionyl chloride, and thereby obtaining a peptide
according to the invention of general formula (I), wherein the
fragments that have the functional groups not involved in the N--C
bond formation are suitably protected with temporary or permanent
protective groups, or alternatively other R.sub.2 radicals may be
introduced by simultaneous incorporation to the cleavage process of
the peptide from the polymeric support.
[0082] A person skilled in the art would easily understand that the
deprotection/cleavage steps of the C-terminal and N-terminal ends
and their subsequent derivatization can be performed in a different
order, according to the processes known in the prior art.
[0083] The term "protective group" relates to a group which blocks
an organic functional group and which can be removed in controlled
conditions. The protective groups, their relative reactivities and
the conditions in which they remain inert are known to the person
skilled in the art.
[0084] Examples of representative protective groups for the amino
group are amides, such as amide acetate, amide benzoate, amide
pivalate; carbamates such as benzyloxycarbonyl (Cbz or Z),
2-chlorobenzyl (CIZ), para-nitrobenzyloxycarbonyl (pNZ),
tert-butyloxycarbonyl (Boc), 2,2,2-trichloroethyloxycarbonyl
(Troc), 2-(trimethylsilyl)ethyloxycarbonyl (Teoc),
9-fluorenylmethyloxycarbonyl (Fmoc) or allyloxycarbonyl (Alloc),
Trityl (Trt), methoxytrityl (Mtt), 2,4-dinitrophenyl (Dnp),
N-[1-(4,4-dimethyl-2,6-dioxocyclohex-1-ylidene)ethyl (Dde),
1-(4,4-dimethyl-2,6-dioxocyclohexylidene)-3-methylbutyl (ivDde),
1-(1-adamantyl)-1-methylethoxycarbonyl (Adpoc), among others,
preferably Boc or Fmoc.
[0085] Examples of representative protective groups for the
carboxyl group are esters, such as the tert-butyl ester (tBu),
allyl ester (All), triphenylmethyl ester (Trt ester), cyclohexyl
ester (cHx), benzyl ester (Bzl), ortho-nitrobenzyl ester,
para-nitrobenzyl ester, para-methoxybenzyl ester,
trimethylsilylethyl ester, 2-phenylisopropyl ester, fluorenylmethyl
ester (Fm),
4-(N41-(4,4-dimethyl-2,6-dioxocyclohexylidene)-3-methylbutyl]amino)benzyl
ester (Dmab), among others; preferred protective groups of the
invention are the All, tBu, cHx, Bzl and Trt esters.
[0086] The side chains of the trifunctional amino acids can be
protected during the synthetic process with temporary or permanent
protective groups orthogonal to the protective groups of the
N-terminal and C-terminal ends.
[0087] The hydroxyl group of the tyrosine side chain can be
protected with the 2-bromobenzyloxycarbonyl group (2-BrZ), tBu,
All, Bzl or 2,6-dichlorobenzyl (2,6-diCIZ) among others. The
histidine side chain can be protected by a protective group
selected from the group formed by Tos, Dnp, methyl (Me), Boc,
benzyloxymethyl (Bom), Bzl, Fmoc, Mts, Trt and Mtt. The amide group
of the glutamine and asparagine side chain can be protected by the
Trt group or xanthyl group (Xan) or can be used unprotected. For
the protection of the carboxyl group of the aspartic acid and
glutamic acid side chain esters can be used such as tBu ester, All
ester, triphenylmethyl ester (Trt ester), cHx ester, Bzl ester,
orto-nitrobenzyl ester, para-nitrobenzyl ester, para-methoxybenzyl
ester, trimethylsilylethyl ester, 2-phenylisopropyl ester, Fm ester
or Dmab ester, among others. The arginine side chain can be
protected by a protective group selected from the group formed by
Tos, 4-methoxy-2,3,6-trimethylbenzenesulfonyl (Mtr), Alloc, nitro,
2,2,4,6,7-pentamethyldihydrobenzofuran-5-sulfonyl (Pbf) and
2,2,5,7,8-pentamethylchroman-6-sulfonyl (Pmc). The indole group of
the tryptophan side chain can be protected by the formyl group
(For), Boc, Mts or can be used unprotected. For the protection of
the amino groups of the lysine side chains amides can be used, such
as amide acetate, amide benzoate, amide pivalate; carbamates such
as Cbz or Z, CIZ, pNZ, Boc, Troc, Teoc, Fmoc or Alloc, Trt, Mtt,
Dnp, Dde, ivDde, Adpoc, among others. The methionine side chain can
be protected in sulfoxide form, in sulfone form or used without
protection. The methionyl(sulfoxide) and methionyl(sulfone) side
chains are not protected.
[0088] In a preferred embodiment, the protective group strategy
used is the strategy wherein the amino groups are protected by Boc,
the carboxyl groups are protected by Bzl, cHx or All, the tyrosine
side chain is protected with 2-BrZ or Bzl, the histidine side chain
is protected by the Tos or Bom group, the aspartic acid and
glutamic acid side chains are protected with Bzl, cHx or All,
glutamine and asparagine are used without protection in their side
chain, methionine is used without protection in its side chain, the
arginine side chain is protected by Tos, the tryptophan side chain
is protected by For or Mts and the lysine side chain is protected
by CIZ, Fmoc or Alloc.
[0089] In another preferred embodiment, the protective group
strategy used is the strategy wherein the amino groups are
protected by Fmoc, the carboxyl groups are protected by the tBu,
All or Trt esters, the tyrosine side chain is protected by tBu, the
histidine side chain is protected by the Trt or Mtt group, the
aspartic acid and glutamic acid side chains are protected with tBu
or All, glutamine and asparagine are protected by the Trt group in
their side chain, methionine is used without protection in its side
chain, the arginine side chain is protected by Pmc or Pbf, the
tryptophan side chain is protected by Boc or is used unprotected,
and the lysine side chain is protected by Boc, Trt or Alloc.
[0090] Examples of these and other additional protective groups,
their introduction and removal, can be found in the literature
[Atherton B. and Sheppard R. C., "Solid Phase Peptide Synthesis: A
practical approach", (1989), IRL Oxford University Press]. The term
"protective groups" also includes the polymeric supports used in
solid phase synthesis.
[0091] When synthesis takes place totally or partially in solid
phase, the possible solid supports used in the procedure of the
invention involve polystyrene supports, polyethylene glycol grafted
to polystyrene and similar, such as and not restricted to,
p-methylbenzhydrylamine resins (MBHA) [Matsueda G. R. et al., "A
p-methylbenzhydrylamine resin for improved solid phase synthesis of
peptide amides", (1981), Peptides, 2, 4550], 2-chlorotrityl resins
[Barlos K. et al., "Darstellung geschutzter PeptidFragmente unter
Einsatz substituierter TriphenylmethylHarze", (1989), Tetrahedron
Lett., 30, 39433946; Barlos K. et al., "Veresterung von partiell
geschutzten PeptidFragmenten mit Harzen. Einsatz von
2-Chlorotritylchlorid zur Synthese von Leu1Gastrin I", (1989),
Tetrahedron Lett., 30, 39473951], TentaGel.RTM. resins (Rapp
Polymere GmbH), ChemMatrix.RTM. resins (Matrix Innovation, Inc.)
and similar, which may or may not include a labile linker, such as
5-(4-aminomethyl-3,5-dimethoxyphenoxy) valeric acid (PAL)
[Albericio F. et al., "Preparation and application of the
5-(4-(9-fluorenylmethyloxycarbonyl)
aminomethyl-3,5-dimethoxy-phenoxy)valeric acid (PAL) handle for the
solid phase synthesis of C-terminal peptide amides under mild
conditions"; (1990), J. Org. Chem., 55, 37303743],
2-[4-aminomethyl-(2,4-dimethoxyphenyl)]phenoxyacetic acid (AM)
[Rink H., "Solid phase synthesis of protected peptide fragments
using a trialkoxy-diphenyl-methylester resin", (1987), Tetrahedron
Lett., 28, 3787-3790], Wang [Wang S. S., "p-Alkoxybenzyl Alcohol
Resin and p-Alkoxybenzyloxycarbonylhydrazide Resin for Solid Phase
Synthesis of Protected Peptide Fragments", (1973), J. Am. Chem.
Soc., 95, 1328-1333] and similar, which enable simultaneous
deprotection and cleavage of the peptide from the polymeric
support.
Cosmetic or Pharmaceutical Compositions of the Invention
[0092] The compounds of the invention can be administered to
inhibit neuronal exocytosis by any means which causes contact
between the compounds and the site of action in a mammal's body,
preferably that of a human being, and in the form of a composition
which contains them.
[0093] To this regard, another aspect of the invention is a
cosmetic or pharmaceutical composition which comprises at least one
compound of general formula (I), its stereoisomers, mixtures
thereof, and/or its cosmetically or pharmaceutically acceptable
salts together with at least one cosmetically or pharmaceutically
acceptable adjuvant. These compositions can be prepared by
conventional means known to persons skilled in the art ["Harry's
Cosmeticology", Seventh edition, (1982), Wilkinson J. B., Moore R.
J., ed. Longman House, Essex, GB].
[0094] The compounds of this invention have variable solubility in
water, according to the nature of their amino acid sequence or any
possible modifications in the N-terminal and/or C-terminal ends.
Therefore, the compounds of this invention can be incorporated into
the compositions by aqueous solution, and those which are not
soluble in water can be solubilized in cosmetically or
pharmaceutically acceptable conventional solvents such as and not
restricted to, ethanol, propanol, isopropanol, propylene glycol,
glycerin, butylene glycol or polyethylene glycol or any combination
thereof.
[0095] The cosmetically or pharmaceutically effective amount of the
compounds of the invention which should be administered, as well as
their dosage, will depend on numerous factors, including age, state
of the patient, the nature or severity of the condition, disorder
or disease to be treated and/or cared for, the route and frequency
of administration and the particular nature of the compounds to be
used.
[0096] "Cosmetically and pharmaceutically effective amount" is
understood to mean a non-toxic but sufficient amount of the
compound or compounds of the invention to provide the desired
effect. The compounds of the invention are used in the cosmetic or
pharmaceutical composition of this invention at cosmetically or
pharmaceutically effective concentrations to achieve the desired
effect; in a preferred form with regards to the total weight of the
composition, between 0.00000001% (in weight) and 20% (in weight);
preferably between 0.000001% (in weight) and 15% (in weight), more
preferably between 0.0001% (in weight) and 10% (in weight) and even
more preferably between 0.0001% (in weight) and 5% (in weight).
[0097] The compounds of general formula (I), their stereoisomers,
mixtures thereof and/or their cosmetic or pharmaceutically
acceptable salts, can also be incorporated into cosmetic or
pharmaceutical delivery systems and/or sustained release
systems.
[0098] The term "delivery systems" relates to a diluent, adjuvant,
excipient or carrier with which the compound of the invention is
administered. These cosmetic or pharmaceutical carriers can be
liquids, such as water, oils or surfactants, including those of
petroleum, animal, plant or synthetic origin, such as and not
restricted to, peanut oil, soybean oil, mineral oil, sesame oil,
castor oil, polysorbates, sorbitan esters, ether sulfates,
sulfates, betaines, glycosides, maltosides, fatty alcohols,
nonoxynols, poloxamers, polyoxyethylenes, polyethylene glycols,
dextrose, glycerol, digitonin and similar. A person skilled in the
art knows the diluents, adjuvants or excipients which can be used
in the different delivery systems in which the compound of the
invention can be administered.
[0099] The term "sustained release" is used in a conventional sense
relating to a delivery system of a compound which provides the
gradual release of this compound during a period of time and
preferably, although not necessarily, with relatively constant
compound release levels over a long period of time.
[0100] Examples of delivery or sustained release systems include,
without restriction, liposomes, mixed liposomes, oleosomes,
niosomes, ethosomes, milliparticles, microparticles, nanoparticles
and solid lipid nanoparticles, nanostructured lipid carriers,
sponges, cyclodextrins, vesicles, micelles, mixed micelles of
surfactants, surfactant-phospholipid mixed micelles, millispheres,
microspheres and nanospheres, lipospheres, millicapsules,
microcapsules and nanocapsules, as well as in microemulsions and
nanoemulsions, which can be added to achieve a greater penetration
of the active principle and/or improve its pharmacokinetic and
pharmacodynamic properties. Preferred delivery or sustained release
systems are liposomes, surfactant-phospholipid mixed micelles,
microemulsions, more preferably water-in-oil microemulsions with an
internal structure of reverse micelle and nanocapsules containing
microemulsions.
[0101] The sustained release systems can be prepared by methods
known in the prior art, and the compositions which contain them can
be administered, for example, by topical or transdermal
administration, including adhesive patches, non-adhesive patches,
occlusive patches and microelectric patches, or by systemic
administration, for example and not restricted to, oral or
parenteral route, including nasal, rectal or subcutaneous
implantation or injection, or direct implantation or injection into
a specific body part, and preferably should release a relatively
constant quantity of the peptides of the invention. The amount of
compound contained in the sustained release system will depend, for
example, on where the composition is to be administered, the
kinetics and duration of the release of the compound of the
invention, as well as the nature of the condition, disorder and/or
disease to be treated and/or cared for.
[0102] The compounds of this invention can also be adsorbed on
solid organic polymers or solid mineral supports such as and not
restricted to, talc, bentonite, silica, starch or maltodextrin
among others.
[0103] The compositions which contain the compounds of general
formula (I), their stereoisomers, mixtures thereof and/or their
cosmetically or pharmaceutically acceptable salts can also be
incorporated into fabrics, non-woven fabrics and medical devices
which are in direct contact with the skin, thus releasing the
compounds of the invention whether by biodegradation of the binding
system to the fabric, non-woven fabric or medical device, or by
friction between them and the body, due to bodily moisture, the
skin's pH or body temperature. Furthermore, the compounds of the
invention can be incorporated into the fabrics and non-woven
fabrics used to make garments that are in direct contact with the
body. Preferably, the fabrics, non-woven fabrics and medical
devices containing the compounds of the invention are used for the
treatment and/or care of conditions, disorders and/or diseases
which improve or are prevented, delayed or hindered by the
inhibition of neuronal exocytosis.
[0104] Examples of fabrics, non-woven fabrics, garments, medical
devices and means for immobilizing the compounds to them, among
which are the delivery systems and/or the sustained release systems
described above, can be found in the literature and are known in
the prior art [Schaab C. K. (1986) HAPPI May 1986; Nelson G.,
"Application of microencapsulation in textiles", (2002), Int. J.
Pharm., 242(1-2), 55-62; "Biofunctional Textiles and the Skin"
(2006) Curr. Probl. Dermatol. v.33, Hipler U. C. and Elsner P.,
eds. S. Karger A G, Basel, Switzerland; Malcolm R. K. et al.,
"Controlled release of a model antibacterial drug from a novel
self-lubricating silicone biomaterial", (2004), J. Cont. Release,
97(2), 313-320]. The preferred fabrics, non-woven fabrics, garments
and medical devices are bandages, gauzes, t-shirts, socks, tights,
underwear, girdles, gloves, diapers, sanitary napkins, dressings,
bedspreads, wipes, adhesive patches, non-adhesive patches,
occlusive patches, microelectric patches and/or face masks.
[0105] The cosmetic or pharmaceutical compositions which contain
the compounds of the invention, their stereoisomers, mixtures
thereof and/or their cosmetically or pharmaceutically acceptable
salts, can be used in different types of compositions of topical or
transdermal application which optionally include cosmetically or
pharmaceutically acceptable excipients necessary for formulating
the desired administration form. A person skilled in the art knows
the different excipients which can be used in the cosmetic or
pharmaceutical compositions which contain the compounds of the
invention.
[0106] The compositions of topical or transdermal application can
be produced in any solid, liquid or semi-solid formulation, such as
and not restricted to, creams, multiple emulsions such as and not
restricted to, oil and/or silicone in water emulsions, water-in-oil
and/or silicone emulsions, water/oil/water or water/silicone/water
type emulsions, and oil/water/oil or silicone/water/silicone type
emulsions, anhydrous compositions, aqueous dispersions, oils,
milks, balsams, foams, lotions, gels, cream gels, hydroalcoholic
solutions, hydroglycolic solutions, hydrogels, liniments, sera,
soaps, shampoos, conditioners, serums, polysaccharide films,
ointments, mousses, pomades, powders, bars, pencils and sprays or
aerosols (sprays), including leave-on and rinse-off formulations.
These topical or transdermal application formulations can be
incorporated using techniques known by the person skilled in the
art into different types of solid accessories such as and not
restricted to, bandages, gauzes, t-shirts, socks, tights,
underwear, girdles, gloves, diapers, sanitary napkins, dressings,
bedspreads, wipes, adhesive patches, non-adhesive patches,
occlusive patches, microelectric patches or face masks, or they can
be incorporated into different make-up products such as make-up
foundation, such as fluid foundations and compact foundations,
make-up removal lotions, make-up removal milks, under-eye
concealers, eye shadows, lipsticks, lip protectors, lip gloss and
powders, among others.
[0107] The cosmetic or pharmaceutical compositions of the invention
may include agents which increase the percutaneous absorption of
the compounds of this invention, such as and not restricted to,
dimethyl sulfoxide, dimethylacetamide, dimethylformamide,
surfactants, azone (1-dodecylazacycloheptane-2-one), alcohol, urea,
ethoxydiglycol, acetone, propylene glycol or polyethylene glycol,
among others. Furthermore, the cosmetic or pharmaceutical
compositions of this invention can be applied to local areas to be
treated by means of iontophoresis, sonophoresis, electroporation,
microelectric patches, mechanical pressure, osmotic pressure
gradient, occlusive cure, microinjections or needle-free injections
by means of pressure, such as injections by oxygen pressure, or any
combination thereof, to achieve a greater penetration of the
compound of the invention. The application area will be determined
by the nature of the condition, disorder and/or disease to be
treated and/or cared for.
[0108] Furthermore, the cosmetic compositions containing the
compounds of general formula (I), their stereoisomers, mixtures
thereof and/or their cosmetically or pharmaceutically acceptable
salts can be used in different types of formulations for oral
administration, preferably in the form of oral cosmetics or drugs,
such as and not restricted to, capsules, including gelatin
capsules, soft capsules, hard capsules, tablets, including sugar
coated tablets, pills, powders, granules, chewing gum, solutions,
suspensions, emulsions, syrups, elixirs, polysaccharide films,
jellies or gelatins, and any other form known by the person skilled
in the art. In a particular embodiment, the compounds of the
invention can be incorporated into any form of functional food or
fortified food, such as and not restricted to, dietary bars or
compact or non-compact powders. These powders can be dissolved in
water, soda, dairy products, soy derivatives or can be incorporated
into dietary bars. The compounds of this invention can be
formulated with common excipients and adjuvants for oral
compositions or food supplements, such as and not restricted to,
fat components, aqueous components, humectants, preservatives,
texturizing agents, flavors, aromas, antioxidants and colorants
common in the food industry.
[0109] Cosmetic or pharmaceutical compositions containing the
compounds of general formula (I), their stereoisomers, mixtures
thereof and/or their cosmetically or pharmaceutically acceptable
salts can also be administered, as well as by topical or
transdermal route, by any other appropriate route, such as oral or
parenteral route, for which they will include the pharmaceutically
acceptable excipients necessary for the formulation of the desired
administration form. In the context of this invention, the term
"parenteral" includes nasal, auricular, ophthalmic, rectal,
urethral, vaginal, subcutaneous, intradermal, intravascular
injections such as intravenous, intramuscular, intraocular,
intravitreous, intracorneal, intraspinal, intramedullary,
intracranial, intracervical, intracerebral, intrameningeal,
intraarticular, intrahepatic, intrathoracic, intratracheal,
intrathecal and intraperitoneal, and any another similar injection
or infusion technique. A person skilled in the art knows the
different means by which the cosmetic or pharmaceutical
compositions which contain the compounds of the invention can be
administered.
[0110] Among the cosmetically or pharmaceutically acceptable
excipients and/or adjuvants contained in the cosmetic or
pharmaceutical compositions described in this invention are
additional ingredients commonly used in cosmetic or pharmaceutical
compositions, such as and not restricted to, other agents which
inhibit neuronal exocytosis, other anticholinergic agents, other
agents which inhibit muscular contraction, other anti-aging agents,
other anti-wrinkle agents, other antiperspirant agents, other
anti-inflammatory agents and/or analgesics, other anti-itching
agents, calming agents, anesthetic agents, inhibitors of
acetylcholine-receptor aggregation, agents that inhibit
acetylcholinesterase, skin relaxant agents, melanin synthesis
stimulating or inhibiting agents, whitening or depigmenting agents,
propigmenting agents, self-tanning agents, NO-synthase inhibiting
agents, 5.alpha.-reductase inhibiting agents, lysyl- and/or prolyl
hydroxylase inhibiting agents, antioxidants, free radical
scavengers and/or agents against atmospheric pollution, reactive
carbonyl species scavengers, anti-glycation agents, antihistamine
agents, antiviral agents, antiparasitic agents, emulsifiers,
emollients, organic solvents, liquid propellants, skin
conditioners, humectants, substances that retain moisture, alpha
hydroxy acids, beta hydroxy acids, moisturizers, epidermal
hydrolytic enzymes, vitamins, amino acids, proteins, pigments or
colorants, dyes, biopolymers, gelling polymers, thickeners,
surfactants, softening agents, emulsifiers, binding agents,
preservatives, agents able to reduce or treat the bags under the
eyes, exfoliating agents, keratolytic agents, flaking agents,
antimicrobial agents, antifungal agents, fungistatic agents,
bactericidal agents, bacteriostatic agents, agents stimulating the
synthesis of dermal or epidermal macromolecules and/or capable of
inhibiting or preventing their degradation, collagen
synthesis-stimulating agents, elastin synthesis-stimulation agents,
decorin synthesis-stimulation agents, laminin synthesis-stimulation
agents, defensin synthesis-stimulating agents, chaperone
synthesis-stimulating agents, cAMP synthesis-stimulating agents,
AQP-3 modulating agents, aquaporin synthesis modulating agents,
proteins from the aquaporin family, hyaluronic acid
synthesis-stimulating agents, glycosaminoglycan
synthesis-stimulating agents, fibronectin synthesis-stimulating
agents, sirtuin synthesis-stimulating agents, sirtuin activating
agents, heat shock proteins, heat shock protein
synthesis-stimulating agents, agents stimulating the synthesis of
lipids and components of the stratum corneum, ceramides, fatty
acids, agents that inhibit collagen degradation, matrix
metalloproteinase inhibitory agents, agents that inhibit elastin
degradation, agents that inhibit serine proteases such as
kallikreins, leukocyte elastase or cathepsin G, agents stimulating
fibroblast proliferation, agents stimulating keratinocyte
proliferation, agents stimulating adipocyte proliferation, agents
stimulating melanocyte proliferation, agents stimulating
keratinocyte differentiation, agents stimulating or delaying
adipocyte differentiation, antihyperkeratosis agents, comedolytic
agents, anti-psoriasis agents, DNA repair agents, DNA protecting
agents, stabilizers, agents for the treatment and/or care of
sensitive skin, firming agents, anti-stretch mark agents, binding
agents, agents regulating sebum production, lipolytic agents or
agents stimulating lipolysis, adipogenic agents, agents modulating
PGC-1.alpha. expression, agents modulating the activity of
PPAR.gamma., agents which increase or reduce the triglyceride
content of adipocytes, anti-cellulite agents, agents which inhibit
the activity of PAR-2, agents stimulating healing, coadjuvant
healing agents, agents stimulating reepithelialization, coadjuvant
reepithelialization agents, cytokine growth factors, agents acting
on capillary circulation and/or microcirculation, agents
stimulating angiogenesis, agents that inhibit vascular
permeability, venotonic agents, agents acting on cell metabolism,
agents to improve dermal-epidermal junction, agents inducing hair
growth, hair growth inhibiting or retardant agents, hair loss
retardant agents, preservatives, perfumes, cosmetic and/or
absorbent and/or body odor masking deodorants, chelating agents,
plant extracts, essential oils, marine extracts, agents obtained
from a biotechnological process, mineral salts, cell extracts,
sunscreens and organic or mineral photoprotective agents active
against ultraviolet A and/or B rays and/or infrared A rays, or
mixtures thereof, provided that they are physically and chemically
compatible with the rest of components in the composition and
particularly with the compounds of the invention. Likewise, the
nature of these additional ingredients should not unacceptably
alter the benefits of the compounds of this invention. The nature
of these additional ingredients can be synthetic or natural, such
as plant extracts, or come from a biotechnological procedure, or
from a combination of a synthetic procedure and a biotechnological
procedure. Additional examples can be found in CTFA International
Cosmetic Ingredient Dictionary & Handbook, 12th Edition (2008).
In the context of this invention, biotechnological procedure is
understood to be any procedure to produce the active ingredient, or
part of it, in an organism, or in part of it.
[0111] An additional aspect of this invention refers to a cosmetic
or pharmaceutical composition which comprises a cosmetically or
pharmaceutically effective quantity of at least one compound
general formula (I), its stereoisomers, mixtures thereof and/or its
cosmetically or pharmaceutically acceptable salts, as well as a
cosmetically or pharmaceutically effective quantity of at least one
extract, synthetic compound or product of biotechnological origin
which is an anti-wrinkle agent and/or anti-aging agent such as and
not restricted to the extracts or hydrolyzed extracts of Vitis
vinifera, Rosa canina, Curcuma longa, Theobroma cacao, Ginkgo
biloba, Leontopodium alpinum or Dunaliella salina among others,
Matrixyl.RTM. [INCI: Palmitoyl Pentapeptide-4], Matrixyl.RTM.
3000.degree. [INCI: Palmitoyl Tetrapeptide-7, Palmitoyl
Oligopeptide], Matrixyl.RTM. Synthe'6.TM. [INCI: Glycerin, Water,
Hydroxypropyl Cyclodextrin, Palmitoyl Tripeptide-38], Essenskin.TM.
[INCI: calcium hydroxymethionine], Renovage [INCI: teprenone],
Resistem.TM. [INCI: Globularia Cordifolia Ferment] or Dermaxyl.RTM.
[INCI: Palmitoyl Oligopeptide] marketed by Sederma/Croda,
Vialox.RTM. [INCI: Pentapeptide-3], Syn.RTM. Ake.RTM. [INCI:
Dipeptide Diaminobutyroyl Benzylamide Diacetate], Syn.RTM.-Coll
[INCI: Palmitoyl Tripeptide-5], Phytaluronate [INCI: Locust Bean
(Ceratonia siliqua) Gum] or Preregen.RTM. [INCI: Glycine soja
(Soybean) Protein, Oxido Reductases] marketed by Pentapharm/DSM,
Myoxinol.TM. [INCI: Hydrolyzed Hibiscus esculentus Extract],
Syniorage.TM. [INCI: Acetyl Tetrapeptide-11], Dermican.TM. [INCI:
Acetyl Tetrapeptide-9] or DN AGE.TM. LS [INCI: Cassia alata leaf
Extract] marketed by Laboratoires Serobiologiques/Cognis/BASF,
Algisum C.RTM. [INCI: Methylsilanol Mannuronate] or
Hydroxyprolisilane CN.RTM. [INCI: Methylsilanol Hydroxyproline
Aspartate] marketed by Exsymol, Argireline.RTM. [INCI: Acetyl
Hexapeptide-8], SNAP-7 [INCI: Acetyl Heptapeptide-4], SNAP-8 [INCI:
Acetyl Octapeptide-3], Leuphasyl.RTM. [INCI: Pentapeptide-18],
Inyline.TM. [INCI: Acetyl Hexapeptide-30], Aldenine.RTM. [INCI:
Hydrolized Wheat Protein, Hydrolized Soy Protein, Tripeptide-1],
Preventhelia.TM. [INCI: Diaminopropionoyl Tripeptide-33],
Decorinyl.RTM. [INCI: Tripeptide-10 Citrulline], Decorinol.RTM.
[INCI: Tripeptide-9 Citrulline], Trylagen.RTM. [INCI:
Pseudoalteromonas Ferment Extract, Hydrolyzed Wheat Protein,
Hydrolyzed Soy Protein, Tripeptide-10 Citrulline, Tripeptide-1],
Eyeseryl.RTM. [INCI: Acetyl Tetrapeptide-5], Peptide AC29 [INCI:
Acetyl Tripeptide-30 Citrulline], Relistase.TM. [INCI:
Acetylarginyltriptophyl Diphenylglycine], Thermostressine.RTM.
[INCI: Acetyl Tetrapeptide-22], Lipochroman.TM. [INCI:
Dimethylmethoxy Chromanol], Chromabright.TM. [INCI: Dimethylmethoxy
Chromanyl Palmitate], Antarcticine.RTM. [INCI: Pseudoalteromonas
Ferment Extract], dGlyage.TM. [INCI: Lysine HCl, Lecithin,
Tripeptide-9 Citrulline], Vilastene.TM. [INCI: Lysine HCl,
Lecithin, Tripeptide-10 Citrulline], Hyadisine.TM. [INCI:
Pseudoalteromonas Ferment Extract], Hyanify.TM. [proposed INCI:
Saccharide Isomerate], Diffuporine.TM. [INCI: Acetyl
Hexapeptide-37], Silusyne.TM. [INCI: Soybean (Glycine Soja) Oil,
Sorbitan Sesquioleate, Isohexadecane, Sodium Hyaluronate,
Lauryldimonium Hydroxypropyl Hydrolized Soy Protein, Acetyl
Hexapeptide-39] or Adifyline.TM.[INCI: Acetyl Hexapeptide-38]
marketed by Lipotec, Kollaren.RTM. [INCI: Tripeptide-1, Dextran]
marketed by Institut Europeen de Biologie Cellulaire, Collaxyl.RTM.
IS [INCI: Hexapeptide-9], Laminixyl IS.TM. [INCI: Heptapeptide],
Orsirtine.TM. GL [INCI: Oryza sativa (Rice) Extract],
D'Orientine.TM. IS [INCI: Phoenix dactylifera (Date) Seed Extract],
Phytoquintescine.TM. [INCI: Einkorn (Triticum monococcum) Extract]
or Quintescine.TM. IS [INCI: Dipeptide-4] marketed by
Vincience/ISP/Ashland, BONT-L-Peptide [INCI: Palmitoyl
Hexapeptide-19] marketed by Infinitec Activos, Deepaline.TM. PVB
[INCI: Palmitoyl hydrolyzed Wheat Protein] or Sepilift.RTM. DPHP
[INCI: Dipalmitoyl Hydroxyproline] marketed by Seppic,
Gatuline.RTM. Expression [INCI: Acmella oleracea Extract],
Gatuline.RTM. In-Tense [INCI: Spilanthes acmella Flower Extract] or
Gatuline.RTM. Age Defense 2 [INCI: Juglans regia (Walnut) Seed
Extract] marketed by Gattefosse, Thalassine.TM. [INCI: Algae
Extract] marketed by Biotechmarine, ChroNOline.TM. [INCI: Caprooyl
Tetrapeptide-3] or Thymulen-4 [INCI: Acetyl Tetrapeptide-2]
marketed by Atrium/Unipex Innovations, EquiStat [INCI: Pyrus malus
Fruit Extract, Glycine soja Seed Extract] or Juvenesce [INCI:
Ethoxydiglicol and Caprylic Triglycerid, Retinol, Ursolic Acid,
Phytonadione, Ilomastat] marketed by Coletica/Engelhard/BASF,
Ameliox [INCI: Carnosine, Tocopherol, Silybum marianum Fruit
Extract] or PhytoCellTec Malus Domestica [INCI: Malus domestica
Fruit Cell Culture] marketed by Mibelle Biochemistry, Bioxilift
[INCI: Pimpinella anisum Extract] or SMS Anti-Wrinkle.RTM. [INCI:
Annona squamosa Seed Extract] marketed by Silab, antagonists of the
Ca.sup.2+ channel such as and not restricted to, alverine,
manganese or magnesium salts, certain secondary or tertiary amines,
retinol and its derivatives, idebenone and its derivatives,
Coenzyme Q10 and its derivatives, boswellic acid and its
derivatives, GHK and its derivatives and/or salts, carnosine and
its derivatives, DNA repair enzymes such as and not restricted to,
photolyase or T4 endonuclease V, or chloride channel agonists among
others, and/or mixtures thereof.
[0112] An additional aspect of this invention relates to a cosmetic
or pharmaceutical composition which comprises a cosmetically or
pharmaceutically effective amount of at least one compound of
general formula (I), its stereoisomers, mixtures thereof and/or its
cosmetically or pharmaceutically acceptable salts, and, in
addition, a cosmetically or pharmaceutically effective amount of at
least one natural extract or essential oil which is an anti-itching
agent, for example and not restricted to, extracts of Abelmoschus
esculentus, Actaea alba, Aglaia odorata, Alkanna tinctoria, Althaea
officinalis, Altingia excelsa, Andropogon virginicus, Aralia
nudicaulis, Aralia racemosa, Argemone mexicana, Barleria prionitis,
Camelia sinensis, Caesalpinia digyna, Campsis grandiflora, Carissa
congesta, Carthamus oxyacantha, Cassia tora, Chrysanthemum indicum,
Cimicifuga racemosa, Cinnamomum camphora, Clematis vitalba, Cuscuta
reflexa, Diospyros peregrina, Enicostema axillare, Hammamelis
virginiana, Jatropha multifida, Lavandula officinalis, Lavandula
latifolia, Liquidambar orientalis, Lithospermum officinale, Madhuca
longifolia, Martynia annua, Medicago sativa, Michelia champaca,
Mikania glomerata, Mimosa pudica, Oryza sativa, Phaseolus vulgaris,
Phyllanthus urinaria, Phyllanthus virgatus, Pistacia vera,
Polygonum hydropiper, Quercus ilex, Rauvolfia caffra, Ricinus
communis, Rubus idaeus, Sagittaria sagittifolia, Sandoricum
koetjape, Sapindus mukorossi, Schleichera oleosa, Sesbania
grandiflora, Spondias dulcis, Tilia sp., Toona ciliata, Tragia
involucrata, Trichosanthes quinquangulata, Vaccaria pyramidata,
Ventilago madraspatana, Veratrum album or Xanthium strumarium among
others or as well as at least one synthetic compound or product of
biotechnological origin which is an anti-itching agent, for example
and not restricted to, mepyramine (pyrilamine), antazoline,
diphenhydramine, carbinoxamine, doxylamine, clemastine,
dimenhydrinate, pheniramine, chlorphenamine (chlorpheniramine),
dexchlorpheniramine, bronpheniramine, triprolidine, cyclizine,
chlorcyclizine, hydroxyzine, meclizine, cetirizine, levocetirizine,
promethazine, thenaldine, alimemazine (trimeprazine),
cyproheptadine, azatidine, ketotifen, acrivastine, astemizole,
cetirizine, loratadine, desloratadine, mizolastine, terfenadine,
fexofenadine, azelastine, levocabastine, olopatadine,
corticosteroids such as cortisone, hydrocortisone, dexamethasone,
prednisone; Neutrazen.TM. [INCI: Water, Butylene Glycol, Dextran,
Palmitoyl Tripeptide-8] marketed by Atrium/Unipex Innovations,
Meliprene.RTM. [INCI: Dextran, Acetil Heptapeptide-1] marketed by
Institut Europeen de Biologie Cellulaire/Unipex Innovations,
Delisens.TM. [proposed INCI: Acetyl Hexapeptide-46] marketed by
Lipotec, Skinasensyl.TM. [INCI: Acetyl Tetrapeptide-15] marketed by
Laboratoires Serobiologiques/Cognis/BASF, SymSitive.RTM. 1609
[INCI: 4-t-Butylcyclohexanol] marketed by Symrise, Symbiocell.TM.
[INCI: Extract from Cestrum Latifolium] marketed by BASF,
Gatuline.RTM. Derma-Sensitive [INCI: Octyldodecyl Myristate,
Capparis Spinosa Fruit Extract] marketed by Gattefosse or MAXnolia
[INCI: Magnolia Officinalis Bark Extract, Vitis Vinifera/Vitis
Vinifera (Grape) Seed Extract, Tocopherol] marketed by Mibelle
Biochemistry among others, or mixtures thereof.
[0113] An additional aspect of this invention relates to a cosmetic
or pharmaceutical composition containing a cosmetically or
pharmaceutically effective quantity of at least one compound of
general formula (I), its stereoisomers, mixtures thereof and/or its
cosmetically or pharmaceutically acceptable salts, and also a
cosmetically or pharmaceutically effective amount of at least one
anti-inflammatory agent and/or analgesic selected, for example and
not restricted to, from the group formed by the extract of
madecassoside, extract of echinacin, amaranth seed oil, sandalwood
oil, peach tree leaf extract, extract of Aloe vera, Arnica montana,
Artemisia vulgaris, Asarum maximum, Calendula officinalis,
Capsicum, Centipeda cunninghamii, Chamomilla recutita, Crinum
asiaticum, Hamamelis virginiana, Harpagophytum procumbens,
Hypericum perforatum, Lilium candidum, Malva sylvestris, Melaleuca
alternifolia, Origanum majorana, Origanum vulgare, Prunus
laurocerasus, Rosmarinus officialis, Salix alba, Silybum marianum,
Tanacetum parthenium, Thymus vulgaris, Uncaria guianensis or
Vaccinum myrtillus, mometasone furoate, prednisolone, non-steroidal
anti-inflammatory drugs including cyclooxygenase or lipoxygenase
inhibitors, benzydamine, acetylsalicylic acid, rosmarinic acid,
ursolic acid, glycyrrhizinate derivatives, .alpha.-bisabolol,
azulene and analogs, sericoside, ruscogenin, escin, escoline, rutin
and analogs, hydrocortisone, clobetasol, dexamethasone,
halobetasol, diflorasone, fluocinonide, amcinonide, triamcinolone,
fluticasone, fluocinolone, flurandrenolide, prednicarbate,
prednisone, paracetamol, amoxiprin, benorilate, choline salicylate,
faislamine, methyl salicylate, magnesium salicylate, salsalate,
diclofenac, aceclofenac, acemetacin, bromfenac, etodolac,
indomethacin, oxamethacin, proglumetacin, sulindac, tolmetin,
ibuprofen, dexibuprofen, carprofen, fenbufen, fenoprofen,
flurbiprofen, ketoprofen, dexketoprofen, ketorolac, loxoprofen,
naproxen, miroprofen, oxaprozin, pranoprofen, tiaprofenic acid,
suprofen, mefenamic acid, meclofenamate, meclofenamic acid,
flufenamic acid, tolfenamic acid, nabumetone, phenylbutazone,
azapropazone, clofezone, kebuzone, metamizole, mofebutazone,
oxyphenbutazone, phenazone, sulfinpyrazone, piroxicam, lornoxicam,
meloxicam, tenoxicam, celecoxib, etoricoxib, lumiracoxib,
parecoxib, rofecoxib, valdecoxib, nimesulide, naproxcinod,
fluproquazone or licofelone, omega-3 and omega-6 fatty acids,
morphine, codeine, oxycodone, hydrocodone, diamorphine, pethidine,
tramadol, buprenorphine, benzocaine, lidocaine, chloroprocaine,
tetracaine, procaine, amitriptyline, carbamazepine, gabapentine,
pregabaline, bisabolol, Neutrazen.TM. [INCI: Water, Butylene
Glycol, Dextran, Palmitoyl Tripeptide-8] marketed by Atrium/Unipex
Innovations, Delisens.TM. [proposed INCI: Acetyl Hexapeptide-46]
marketed by Lipotec, Meliprene.RTM. [INCI: Dextran, Acetyl
Heptapeptide-1] marketed by Institut Europeen de Biologie
Cellulaire/Unipex Innovations, Skinasensyl.TM. [INCI: Acetyl
Tetrapeptide-15] or Anasensyl.TM. [INCI: Mannitol, Ammonium
Glycyrrhizate, Caffeine, Hippocastanum (Horse Chestnut) Extract]
marketed by Laboratoires Serobiologiques/Cognis/BASF,
Calmosensine.TM. [INCI: Acetyl Dipeptide-1] marketed by
Sederma/Croda, coenzyme Q10 or alkylglycerin ethers, among others,
or mixtures thereof.
[0114] Another additional aspect of this invention relates to a
cosmetic or pharmaceutical composition containing a cosmetically or
pharmaceutically effective quantity of at least one compound of
general formula (I), its stereoisomers, mixtures thereof and/or its
cosmetically or pharmaceutically acceptable salts, and also a
cosmetically or pharmaceutically effective amount of at least one
agent which inhibits neuronal exocytosis, anticholinergic agent,
inhibitor of acetylcholine-receptor aggregation and/or a muscle
contraction inhibitor selected, for example and not restricted to,
from the group formed by extracts of Atropa belladonna, Hyoscyamus
niger, Mandragora officinarum, Chondodendron tomentosum, plants
from the Brugmansias genus, or from the Daturas genus, Clostridium
botulinum toxin, peptides derived from the protein SNAP-25,
peptides derived from the protein synaptotagmin, peptides derived
from the protein syntaxin, peptides derived from the protein
synaptobrevin, peptides derived from the protein snapin, baclofen,
carbidopa, levodopa, bromocriptine, chlorphenesin, chlorzoxazone,
donepezil, mephenoxalone, reserpine, tetrabenazine, dantrolene,
thiocolchicoside, tizanidine, chlonidine, procyclidine,
glycopyrrolate, atropine, hyoscyamine, benztropine, scopolamine,
prometazine, diphenhydramine, dimenhydrinate, dicyclomine,
cyclobenzaprine, orphenadrine, flavoxate, cyclopentolate,
ipratropium, oxybutynin, pirenzepine, tiotropium, trihexyphenidyl,
tolterodine, tropicamide, solifenacin, darifenacin, mebeverine,
trimethaphan, atracurium, cisatracurium, doxacurium, fazadinium,
metocurine, mivacurium, pancuronium, pipecuronium, rapacuronium,
tubocuranine, dimethyl tubocuranine, rocuronium, vecuronium,
suxamethonium, 18-methoxycoronaridine, carisoprodol, febarbamate,
meprobamate, metocarbamol, phenprobamate, tibamate, anticonvulsant
agents such as levetiracetam, stiripentol, phenobarbital,
methylphenobarbital, pentobarbital, metarbital, barbexaclone,
primidone, carbamazepine, oxcarbazepine, benzodiazepines, for
example and not restricted to, clonazepam, cloxazolam, clorazepate,
diazepam, flutoprazepam, lorazepam, midazolam, nitrazepam,
nimetazepam, fenazepam, temazepam, tetrazepam, clobazam,
Argireline.RTM. [INCI: Acetyl Hexapeptide-8], SNAP-7 [INCI: Acetyl
Heptapeptide-4], SNAP-8 [INCI: Acetyl Octapeptide-3],
Leuphasyl.RTM. [INCI: Pentapeptide-18] or Inyline.TM. [INCI: Acetyl
Hexapeptide-30] marketed by Lipotec, BONT-L-Peptide [INCI:
Palmitoyl Hexapeptide-19] marketed by Infinitec Activos, and
Vialox.RTM. [INCI: Pentapeptide-3] or Syn.RTM. Ake.RTM. [INCI:
Dipeptide Diaminobutyroyl Benzylamide Diacetate] marketed by
Pentapharm/DSM among others, or mixtures thereof.
[0115] Another additional aspect of this invention relates to a
cosmetic or pharmaceutical composition containing a cosmetically or
pharmaceutically effective quantity of at least one compound of
general formula (I), its stereoisomers, mixtures thereof and/or its
cosmetically or pharmaceutically acceptable salts, and also a
cosmetically or pharmaceutically effective amount of at least one
cosmetic and/or absorbent and/or body odor masking deodorant and/or
antiperspirant agent, perfume and/or perfumed oil selected, for
example and not restricted to, from the group formed by the complex
zinc salt of ricinoleic acid, derived from abiotic acid, salvia
essence, chamomile essence, carnation essence, lemon balm essence,
mint essence, cinnamon leaf essence, lime blossom essence, juniper
berry essence, vetiver essence, frankincense essence, galbanum
essence, labdanum essence, lavender essence, peppermint essence,
benzoin, bergamot, dihydromyrcenol, lilial, lyral, citronellol,
lemon essence, mandarin essence, orange essence, lavender essence,
muscatel, geranium bourbon essence, aniseed, cilantro, cumin,
juniper, extracts of fleur-de-lis, lily, roses, jasmine, neroli;
benzyl acetate, p-tert-butylcyclohexyl acetate, linalyl acetate,
phenylethyl acetate, ethylmethylphenyl glycinate, linalyl benzoate,
benzyl formiate, alylcyclohexyl propionate, stiralyl propionate,
benzyl salicylate, benzylethylether, linear alkanes with from 8 to
18 carbon atoms, citral, ricinoleic acid, citronellal, citronellyl
oxyacetaldehyde, cyclamen aldehyde, hydroxycitronellal, bourgeonal,
ionones, methyl cedryl ketone, anethole, eugenol, isoeugenol,
geraniol, linalool, terpineol, phenylethylalcohol,
.alpha.-hexylcinnamaldehyde, geraniol, benzylacetone,
cyclamenaldehyde, ambroxan, indole, hedione, sandelice,
cyclovertal, .beta.-damascone, allyl amyl glycolate,
dihydromyrcenol, phenoxyethyl isobutyrate, cyclohexyl salicylate,
phenylacetic acid, geranyl acetate, romilate, irotyl, floramate,
aluminum salts such as alum, aluminum chloride, aluminum
chlorohydrate, aluminum dichlorohydrate, aluminum
sesquichlorohydrate, aluminum hydroxy allantoinate, aluminum
chlorotartrate, aluminum and zirconium trichlorohydrate, aluminum
and zirconium tetrachlorohydrate, aluminum and zirconium
pentachlorohydrate and/or mixtures thereof, Leuphasyl.RTM. [INCI:
Pentapeptide-18], SNAP-7 [INCI: Acetyl Heptapeptide-4], SNAP-8
[INCI: Acetyl Octapeptide-3], Argireline.RTM. [INCI: Acetyl
Hexapeptide-8] or Inyline.TM. [INCI: Acetyl Hexapeptide-30]
marketed by Lipotec, Vialox.RTM. [INCI: Pentapeptide 3] or Syn.RTM.
Ake.RTM. [INCI: Dipeptide Diaminobutyroyl Benzylamide Diacetate]
marketed by Pentapharm/DSM and BONT-L-Peptide [INCI: Palmitoyl
Hexapeptide-19] marketed by Infinitec Activos among others, or
mixtures thereof.
Applications
[0116] In another aspect, this invention relates to a compound of
general formula (I):
R.sub.1--W.sub.n--X.sub.m-AA.sub.1-AA.sub.2-AA.sub.3-AA.sub.4-AA.sub.5-A-
A.sub.6-AA.sub.7-Y.sub.p--Z.sub.q--R.sub.2 (I)
its stereoisomers, mixtures thereof and/or its cosmetically or
pharmaceutically acceptable salts, characterized in that: [0117]
AA.sub.1 is selected from the group formed by -Arg-, -His-, -Lys-,
-Gln-, -Asn-, -Glu- and -Asp-; [0118] AA.sub.2 is selected from the
group formed by -His-, -Gln-, -Asn-, -Glu- and -Asp-; [0119]
AA.sub.3 is selected from the group formed by -Leu-, -Ile-, -Phe-
and -Tyr-; [0120] AA.sub.4 is selected from the group formed by
-Lys-, -His-, -Arg-, -Gln-, -Leu-, -Ile-, -Met-, -MetO-- and
-MetO.sub.2--; [0121] AA.sub.5 is selected from the group formed by
-Arg-, -His-, -Lys-, -Gln-, -Asn-, -Glu- and -Asp-; [0122] AA.sub.6
is selected from the group formed by -Phe-, -Trp-, -Ile- and -Val-;
[0123] AA.sub.7 is selected from the group formed by -Met-, -MetO--
and -MetO.sub.2--; [0124] W, X, Y, Z are amino acids and are
independently selected from amongst themselves; [0125] n, m, p and
q are independently selected from amongst themselves and have a
value of 0 or 1; [0126] n+m+p+q is smaller or equal to 2; [0127]
with the condition that it is not SEQ ID NO:111; [0128] R.sub.1 is
selected from the group formed by H, a polymer derived from
polyethylene glycol, substituted or unsubstituted non-cyclic
aliphatic group, substituted or unsubstituted alicyclyl,
substituted or unsubstituted heterocyclyl, substituted or
unsubstituted heteroarylalkyl, substituted or unsubstituted aryl,
substituted or unsubstituted aralkyl and R.sub.5--CO--, wherein
R.sub.5 is selected from the group formed by H, substituted or
unsubstituted non-cyclic aliphatic group, substituted or
unsubstituted alicyclyl, substituted or unsubstituted aryl,
substituted or unsubstituted aralkyl, substituted or unsubstituted
heterocyclyl and substituted or unsubstituted heteroarylalkyl;
[0129] R.sub.2 is selected from the group formed by
--NR.sub.3R.sub.4, --OR.sub.3 and --SR.sub.3, wherein R.sub.3 and
R.sub.4 are independently selected from the group formed by H, a
polymer derived from polyethylene glycol, substituted or
unsubstituted non-cyclic aliphatic group, substituted or
unsubstituted alicyclyl, substituted or unsubstituted heterocyclyl,
substituted or unsubstituted heteroarylalkyl, substituted or
unsubstituted aryl, substituted or unsubstituted aralkyl; and
[0130] R.sub.1 and R.sub.2 are not .alpha.-amino acids, for its use
in medicine.
[0131] In another aspect, the invention relates to a compound of
general formula (I):
R.sub.1--W.sub.n--X.sub.m-AA.sub.1-AA.sub.2-AA.sub.3-AA.sub.4-AA.sub.5-A-
A.sub.6-AA.sub.7-Y.sub.p--Z.sub.q--R.sub.2 (I)
[0132] its stereoisomers, mixtures thereof and/or its cosmetically
or pharmaceutically acceptable salts, characterized in that: [0133]
AA.sub.1 is selected from the group formed by -Arg-, -His-, -Lys-,
-Gln-, -Asn-, -Glu- and -Asp-; [0134] AA.sub.2 is selected from the
group formed by -His-, -Gln-, -Asn-, -Glu- and -Asp-; [0135]
AA.sub.3 is selected from the group formed by -Leu-, -Ile-, -Phe-
and -Tyr-; [0136] AA.sub.4 is selected from the group formed by
-Lys-, -His-, -Arg-, -Gln-, -Leu-, -Ile-, -Met-, -MetO-- and
-MetO.sub.2--; [0137] AA.sub.5 is selected from the group formed by
-Arg-, -His-, -Lys-, -Gln-, -Asn-, -Glu- and -Asp-; [0138] AA.sub.6
is selected from the group formed by -Phe-, -Trp-, -Ile- and -Val-;
[0139] AA.sub.7 is selected from the group formed by -Met-, -MetO--
and -MetO.sub.2--; [0140] W, X, Y, Z are amino acids and are
independently selected from amongst themselves; [0141] n, m, p and
q are independently selected from amongst themselves and have a
value of 0 or 1; [0142] n+m+p+q is smaller or equal to 2; [0143]
R.sub.1 is selected from the group formed by H, a polymer derived
from polyethylene glycol, substituted or unsubstituted non-cyclic
aliphatic group, substituted or unsubstituted alicyclyl,
substituted or unsubstituted heterocyclyl, substituted or
unsubstituted heteroarylalkyl, substituted or unsubstituted aryl,
substituted or unsubstituted aralkyl and R.sub.5--CO--, wherein
R.sub.5 is selected from the group formed by H, substituted or
unsubstituted non-cyclic aliphatic group, substituted or
unsubstituted alicyclyl, substituted or unsubstituted aryl,
substituted or unsubstituted aralkyl, substituted or unsubstituted
heterocyclyl and substituted or unsubstituted heteroarylalkyl;
[0144] R.sub.2 is selected from the group formed by
--NR.sub.3R.sub.4, --OR.sub.3 and --SR.sub.3, wherein R.sub.3 and
R.sub.4 are independently selected from the group formed by H, a
polymer derived from polyethylene glycol, substituted or
unsubstituted non-cyclic aliphatic group, substituted or
unsubstituted alicyclyl, substituted or unsubstituted heterocyclyl,
substituted or unsubstituted heteroarylalkyl, substituted or
unsubstituted aryl, substituted or unsubstituted aralkyl; and
[0145] R.sub.1 and R.sub.2 are not .alpha.-amino acids, for its use
in the treatment and/or prevention, delaying or hindering of pain,
inflammation, itching, hyperhidrosis and/or of neurological,
compulsive and/or neuropsychiatric diseases and/or disorders which
are improved by the inhibition of neuronal exocytosis, selected
from the group formed by muscular spasticity, dystonia, focal
dystonia, blepharospasm, torsion dystonia, cervical dystonia or
torticollis, laryngeal dystonia or spasmodic dysphonia,
oromandibular dystonia, extremity dystonia, writer's cramp,
musician's cramp, foot dystonia, bruxism, facial scoliosis,
hemifacial spasm, tics, strabismus, segmentary dystonia, Meige's
syndrome, multifocal dystonia, hemidystonia, dopamine-responsive
dystonia, Segawa's dystonia, trembling, Parkinson's disease, nerve
impingements, Alzheimer's disease and Tourette's syndrome.
[0146] In another aspect, the invention relates to a compound of
general formula (I):
R.sub.1--W.sub.n--X.sub.m-AA.sub.1-AA.sub.2-AA.sub.3-AA.sub.4-AA.sub.5-A-
A.sub.6-AA.sub.7-Y.sub.p--Z.sub.q--R.sub.2 (I)
its stereoisomers, mixtures thereof and/or its cosmetically or
pharmaceutically acceptable salts, characterized in that: [0147]
AA.sub.1 is selected from the group formed by -Arg-, -His-, -Lys-,
-Gln-, -Asn-, -Glu- and -Asp-; [0148] AA.sub.2 is selected from the
group formed by -His-, -Gln-, -Asn-, -Glu- and -Asp-; [0149]
AA.sub.3 is selected from the group formed by -Leu-, -Ile-, -Phe-
and -Tyr-; [0150] AA.sub.4 is selected from the group formed by
-Lys-, -His-, -Arg-, -Gln-, -Leu-, -Ile-, -Met-, -MetO-- and
-MetO.sub.2--; [0151] AA.sub.5 is selected from the group formed by
-Arg-, -His-, -Lys-, -Gln-, -Asn-, -Glu- and -Asp-; [0152] AA.sub.6
is selected from the group formed by -Phe-, -Trp-, -Ile- and -Val-;
[0153] AA.sub.7 is selected from the group formed by -Met-, -MetO--
and -MetO.sub.2--; [0154] W, X, Y, Z are amino acids and are
independently selected from amongst themselves; [0155] n, m, p and
q are independently selected from amongst themselves and have a
value of 0 or 1; [0156] n+m+p+q is smaller or equal to 2; [0157]
R.sub.1 is selected from the group formed by H, a polymer derived
from polyethylene glycol, substituted or unsubstituted non-cyclic
aliphatic group, substituted or unsubstituted alicyclyl,
substituted or unsubstituted heterocyclyl, substituted or
unsubstituted heteroarylalkyl, substituted or unsubstituted aryl,
substituted or unsubstituted aralkyl and R.sub.5--CO--, wherein
R.sub.5 is selected from the group formed by H, substituted or
unsubstituted non-cyclic aliphatic group, substituted or
unsubstituted alicyclyl, substituted or unsubstituted aryl,
substituted or unsubstituted aralkyl, substituted or unsubstituted
heterocyclyl and substituted or unsubstituted heteroarylalkyl;
[0158] R.sub.2 is selected from the group formed by
--NR.sub.3R.sub.4, --OR.sub.3 and --SR.sub.3, wherein R.sub.3 and
R.sub.4 are independently selected from the group formed by H, a
polymer derived from polyethylene glycol, substituted or
unsubstituted non-cyclic aliphatic group, substituted or
unsubstituted alicyclyl, substituted or unsubstituted heterocyclyl,
substituted or unsubstituted heteroarylalkyl, substituted or
unsubstituted aryl, substituted or unsubstituted aralkyl; and
[0159] R.sub.1 and R.sub.2 are not .alpha.-amino acids, for its use
in the treatment of the skin, hair and/or mucous membranes.
[0160] In another aspect, the invention relates to the use of a
compound of general formula (I):
R.sub.1--W.sub.n--X.sub.m-AA.sub.1-AA.sub.2-AA.sub.3-AA.sub.4-AA.sub.5-A-
A.sub.6-AA.sub.7-Y.sub.p--Z.sub.q--R.sub.2 (I)
its stereoisomers, mixtures thereof and/or its cosmetically or
pharmaceutically acceptable salts, characterized in that: [0161]
AA.sub.1 is selected from the group formed by -Arg-, -His-, -Lys-,
-Gln-, -Asn-, -Glu- and -Asp-; [0162] AA.sub.2 is selected from the
group formed by -His-, -Gln-, -Asn-, -Glu- and -Asp-; [0163]
AA.sub.3 is selected from the group formed by -Leu-, -Ile-, -Phe-
and -Tyr-; [0164] AA.sub.4 is selected from the group formed by
-Lys-, -His-, -Arg-, -Gin-, -Leu-, -Ile-, -Met-, -MetO-- and
-MetO.sub.2--; [0165] AA.sub.5 is selected from the group formed by
-Arg-, -His-, -Lys-, -Gln-, -Asn-, -Glu- and -Asp-; [0166] AA.sub.6
is selected from the group formed by -Phe-, -Trp-, -Ile- and -Val-;
[0167] AA.sub.7 is selected from the group formed by -Met-, -MetO--
and -MetO.sub.2--; [0168] W, X, Y, Z are amino acids and are
independently selected from amongst themselves; [0169] n, m, p and
q are independently selected from amongst themselves and have a
value of 0 or 1; [0170] n+nn+p+q is smaller or equal to 2; [0171]
R.sub.1 is selected from the group formed by H, a polymer derived
from polyethylene glycol, substituted or unsubstituted non-cyclic
aliphatic group, substituted or unsubstituted alicyclyl,
substituted or unsubstituted heterocyclyl, substituted or
unsubstituted heteroarylalkyl, substituted or unsubstituted aryl,
substituted or unsubstituted aralkyl and R.sub.5--CO--, wherein
R.sub.5 is selected from the group formed by H, substituted or
unsubstituted non-cyclic aliphatic group, substituted or
unsubstituted alicyclyl, substituted or unsubstituted aryl,
substituted or unsubstituted aralkyl, substituted or unsubstituted
heterocyclyl and substituted or unsubstituted heteroarylalkyl;
[0172] R.sub.2 is selected from the group formed by
--NR.sub.3R.sub.4, --OR.sub.3 and --SR.sub.3, wherein R.sub.3 and
R.sub.4 are independently selected from the group formed by H, a
polymer derived from polyethylene glycol, substituted or
unsubstituted non-cyclic aliphatic group, substituted or
unsubstituted alicyclyl, substituted or unsubstituted heterocyclyl,
substituted or unsubstituted heteroarylalkyl, substituted or
unsubstituted aryl, substituted or unsubstituted aralkyl; and
[0173] R.sub.1 and R.sub.2 are not .alpha.-amino acids, for the
cosmetic, non-therapeutic treatment and/or care of the skin, hair
and/or mucous membranes, in particular for the prevention, delay or
hindering of aging and/or photoaging of the skin, hair and/or
mucous membranes, the treatment and/or prevention, delay or
hindering of wrinkles and/or expression wrinkles, treatment and/or
prevention, delay or hindering of perspiration, treatment and/or
care of disorders of the skin selected from the group formed by
calluses, warts, treatment stimulating hair growth and/or
prevention, delay or hindering of hair loss.
[0174] In another aspect the invention relates to a compound of
general formula (I):
R.sub.1--W.sub.n--X.sub.m-AA.sub.1-AA.sub.2-AA.sub.3-AA.sub.4-AA.sub.5-A-
A.sub.6-AA.sub.7-Y.sub.p--Z.sub.q--R.sub.2 (I)
its stereoisomers, mixtures thereof and/or its cosmetically or
pharmaceutically acceptable salts, characterized in that: [0175]
AA.sub.1 is selected from the group formed by -Arg-, -His-, -Lys-,
-Gln-, -Asn-, -Glu- and -Asp-; [0176] AA.sub.2 is selected from the
group formed by -His-, -Gln-, -Asn-, -Glu- and -Asp-; [0177]
AA.sub.3 is selected from the group formed by -Leu-, -Ile-, -Phe-
and -Tyr-; [0178] AA.sub.4 is selected from the group formed by
-Lys-, -His-, -Arg-, -Gin-, -Leu-, -Ile-, -Met-, -MetO-- and
-MetO.sub.2--; [0179] AA.sub.5 is selected from the group formed by
-Arg-, -His-, -Lys-, -Gln-, -Asn-, -Glu- and -Asp-; [0180] AA.sub.6
is selected from the group formed by -Phe-, -Trp-, -Ile- and -Val-;
[0181] AA.sub.7 is selected from the group formed by -Met-, -MetO--
and -MetO.sub.2--; [0182] W, X, Y, Z are amino acids and are
independently selected from amongst themselves; [0183] n, m, p and
q are independently selected from amongst themselves and have a
value of 0 or 1; [0184] n+m+p+q is smaller or equal to 2; [0185]
R.sub.1 is selected from the group formed by H, a polymer derived
from polyethylene glycol, substituted or unsubstituted non-cyclic
aliphatic group, substituted or unsubstituted alicyclyl,
substituted or unsubstituted heterocyclyl, substituted or
unsubstituted heteroarylalkyl, substituted or unsubstituted aryl,
substituted or unsubstituted aralkyl and R.sub.5--CO--, wherein
R.sub.5 is selected from the group formed by H, substituted or
unsubstituted non-cyclic aliphatic group, substituted or
unsubstituted alicyclyl, substituted or unsubstituted aryl,
substituted or unsubstituted aralkyl, substituted or unsubstituted
heterocyclyl and substituted or unsubstituted heteroarylalkyl;
[0186] R.sub.2 is selected from the group formed by
--NR.sub.3R.sub.4, --OR.sub.3 and --SR.sub.3, wherein R.sub.3 and
R.sub.4 are independently selected from the group formed by H, a
polymer derived from polyethylene glycol, substituted or
unsubstituted non-cyclic aliphatic group, substituted or
unsubstituted alicyclyl, substituted or unsubstituted heterocyclyl,
substituted or unsubstituted heteroarylalkyl, substituted or
unsubstituted aryl, substituted or unsubstituted aralkyl; and
[0187] R.sub.1 and R.sub.2 are not .alpha.-amino acids, for its use
in the inhibition of neuronal exocytosis.
[0188] Alternatively, in another aspect, the invention relates to a
method of treatment and/or prevention, delay or hindering of pain,
inflammation, itching, hyperhidrosis and/or of neurological,
compulsive and/or neuropsychiatric diseases and/or disorders which
are improved by the inhibition of neuronal exocytosis, selected
from the group formed by muscular spasticity, dystonia, focal
dystonia, blepharospasm, torsion dystonia, cervical dystonia or
torticollis, laryngeal dystonia or spasmodic dysphonia,
oromandibular dystonia, extremity dystonia, writer's cramp,
musician's cramp, foot dystonia, bruxism, facial scoliosis,
hemifacial spasm, tics, strabismus, segmentary dystonia, Meige's
syndrome, multifocal dystonia, hemidystonia, dopamine-responsive
dystonia, Segawa's dystonia, trembling, Parkinson's disease, nerve
impingements, Alzheimer's disease and Tourette's syndrome, which
comprises the administration of a cosmetically or pharmaceutically
effective quantity of at least one compound of general formula
(I):
R.sub.1--W.sub.n--X.sub.m-AA.sub.1-AA.sub.2-AA.sub.3-AA.sub.4-AA.sub.5-A-
A.sub.6-AA.sub.7-Y.sub.p--Z.sub.q--R.sub.2 (I)
[0189] its stereoisomers, mixtures thereof and/or its cosmetically
or pharmaceutically acceptable salts, characterized in that: [0190]
AA.sub.1 is selected from the group formed by -Arg-, -His-, -Lys-,
-Gln-, -Asn-, -Glu- and -Asp-; [0191] AA.sub.2 is selected from the
group formed by -His-, -Gln-, -Asn-, -Glu- and -Asp-; [0192]
AA.sub.3 is selected from the group formed by -Leu-, -Ile-, -Phe-
and -Tyr-; [0193] AA.sub.4 is selected from the group formed by
-Lys-, -His-, -Arg-, -Gln-, -Leu-, -Ile-, -Met-, -MetO-- and
-MetO.sub.2--; [0194] AA.sub.5 is selected from the group formed by
-Arg-, -His-, -Lys-, -Gln-, -Asn-, -Glu- and -Asp-; [0195] AA.sub.6
is selected from the group formed by -Phe-, -Trp-, -Ile- and -Val-;
[0196] AA.sub.7 is selected from the group formed by -Met-, -MetO--
and -MetO.sub.2--; [0197] W, X, Y, Z are amino acids and are
independently selected from amongst themselves; [0198] n, m, p and
q are independently selected from amongst themselves and have a
value of 0 or 1; [0199] n+m+p+q is smaller or equal to 2; [0200]
R.sub.1 is selected from the group formed by H, a polymer derived
from polyethylene glycol, substituted or unsubstituted non-cyclic
aliphatic group, substituted or unsubstituted alicyclyl,
substituted or unsubstituted heterocyclyl, substituted or
unsubstituted heteroarylalkyl, substituted or unsubstituted aryl,
substituted or unsubstituted aralkyl and R.sub.5--CO--, wherein
R.sub.5 is selected from the group formed by H, substituted or
unsubstituted non-cyclic aliphatic group, substituted or
unsubstituted alicyclyl, substituted or unsubstituted aryl,
substituted or unsubstituted aralkyl, substituted or unsubstituted
heterocyclyl and substituted or unsubstituted heteroarylalkyl;
[0201] R.sub.2 is selected from the group formed by
--NR.sub.3R.sub.4, --OR.sub.3 and --SR.sub.3, wherein R.sub.3 and
R.sub.4 are independently selected from the group formed by H, a
polymer derived from polyethylene glycol, substituted or
unsubstituted non-cyclic aliphatic group, substituted or
unsubstituted alicyclyl, substituted or unsubstituted heterocyclyl,
substituted or unsubstituted heteroarylalkyl, substituted or
unsubstituted aryl, substituted or unsubstituted aralkyl; and
[0202] R.sub.1 and R.sub.2 are not .alpha.-amino acids.
[0203] In another aspect, the invention relates to a method of
treatment and/or care of the skin, hair and/or mucous membranes
which comprises the administration of a cosmetically or
pharmaceutically effective quantity of at least one compound of
general formula (I):
R.sub.1--W.sub.n--X.sub.m-AA.sub.1-AA.sub.2-AA.sub.3-AA.sub.4-AA.sub.5-A-
A.sub.6-AA.sub.7-Y.sub.p--Z.sub.q--R.sub.2 (I)
its stereoisomers, mixtures thereof and/or its cosmetically or
pharmaceutically acceptable salts, characterized in that: [0204]
AA.sub.1 is selected from the group formed by -Arg-, -His-, -Lys-,
-Gln-, -Asn-, -Glu- and -Asp-; [0205] AA.sub.2 is selected from the
group formed by -His-, -Gln-, -Asn-, -Glu- and -Asp-; [0206]
AA.sub.3 is selected from the group formed by -Leu-, -Ile-, -Phe-
and -Tyr-; [0207] AA.sub.4 is selected from the group formed by
-Lys-, -His-, -Arg-, -Gln-, -Leu-, -Ile-, -Met-, -MetO-- and
-MetO.sub.2--; [0208] AA.sub.5 is selected from the group formed by
-Arg-, -His-, -Lys-, -Gln-, -Asn-, -Glu- and -Asp-; [0209] AA.sub.6
is selected from the group formed by -Phe-, -Trp-, -Ile- and -Val-;
[0210] AA.sub.7 is selected from the group formed by -Met-, -MetO--
and -MetO.sub.2--; [0211] W, X, Y, Z are amino acids and are
independently selected from amongst themselves; [0212] n, m, p and
q are independently selected from amongst themselves and have a
value of 0 or 1; [0213] n+m+p+q is smaller or equal to 2; [0214]
R.sub.1 is selected from the group formed by H, a polymer derived
from polyethylene glycol, substituted or unsubstituted non-cyclic
aliphatic group, substituted or unsubstituted alicyclyl,
substituted or unsubstituted heterocyclyl, substituted or
unsubstituted heteroarylalkyl, substituted or unsubstituted aryl,
substituted or unsubstituted aralkyl and R.sub.5--CO--, wherein
R.sub.5 is selected from the group formed by H, substituted or
unsubstituted non-cyclic aliphatic group, substituted or
unsubstituted alicyclyl, substituted or unsubstituted aryl,
substituted or unsubstituted aralkyl, substituted or unsubstituted
heterocyclyl and substituted or unsubstituted heteroarylalkyl;
[0215] R.sub.2 is selected from the group formed by
--NR.sub.3R.sub.4, --OR.sub.3 and --SR.sub.3, wherein R.sub.3 and
R.sub.4 are independently selected from the group formed by H, a
polymer derived from polyethylene glycol, substituted or
unsubstituted non-cyclic aliphatic group, substituted or
unsubstituted alicyclyl, substituted or unsubstituted heterocyclyl,
substituted or unsubstituted heteroarylalkyl, substituted or
unsubstituted aryl, substituted or unsubstituted aralkyl; and
[0216] R.sub.1 and R.sub.2 are not .alpha.-amino acids.
[0217] In another aspect the invention relates to a method of
inhibition of neuronal exocytosis which comprises the
administration of a cosmetically or pharmaceutically effective
quantity of at least a compound of general formula (I):
R.sub.1--W.sub.n--X.sub.m-AA.sub.1-AA.sub.2-AA.sub.3-AA.sub.4-AA.sub.5-A-
A.sub.6-AA.sub.7-Y.sub.p--Z.sub.q--R.sub.2 (I)
[0218] its stereoisomers, mixtures thereof and/or its cosmetically
or pharmaceutically acceptable salts, characterized in that: [0219]
AA.sub.1 is selected from the group formed by -Arg-, -His-, -Lys-,
-Gln-, -Asn-, -Glu- and -Asp-; [0220] AA.sub.2 is selected from the
group formed by -His-, -Gln-, -Asn-, -Glu- and -Asp-; [0221]
AA.sub.3 is selected from the group formed by -Leu-, -Ile-, -Phe-
and -Tyr-; [0222] AA.sub.4 is selected from the group formed by
-Lys-, -His-, -Arg-, -Gln-, -Leu-, -Ile-, -Met-, -MetO-- and
-MetO.sub.2--; [0223] AA.sub.5 is selected from the group formed by
-Arg-, -His-, -Lys-, -Gln-, -Asn-, -Glu- and -Asp-; [0224] AA.sub.6
is selected from the group formed by -Phe-, -Trp-, -Ile- and -Val-;
[0225] AA.sub.7 is selected from the group formed by -Met-, -MetO--
and -MetO.sub.2--; [0226] W, X, Y, Z are amino acids and are
independently selected from amongst themselves; [0227] n, m, p and
q are independently selected from amongst themselves and have a
value of 0 or 1; [0228] n+m+p+q is smaller or equal to 2; [0229]
R.sub.1 is selected from the group formed by H, a polymer derived
from polyethylene glycol, substituted or unsubstituted non-cyclic
aliphatic group, substituted or unsubstituted alicyclyl,
substituted or unsubstituted heterocyclyl, substituted or
unsubstituted heteroarylalkyl, substituted or unsubstituted aryl,
substituted or unsubstituted aralkyl and R.sub.5--CO--, wherein
R.sub.5 is selected from the group formed by H, substituted or
unsubstituted non-cyclic aliphatic group, substituted or
unsubstituted alicyclyl, substituted or unsubstituted aryl,
substituted or unsubstituted aralkyl, substituted or unsubstituted
heterocyclyl and substituted or unsubstituted heteroarylalkyl;
[0230] R.sub.2 is selected from the group formed by
--NR.sub.3R.sub.4, --OR.sub.3 and --SR.sub.3, wherein R.sub.3 and
R.sub.4 are independently selected from the group formed by H, a
polymer derived from polyethylene glycol, substituted or
unsubstituted non-cyclic aliphatic group, substituted or
unsubstituted alicyclyl, substituted or unsubstituted heterocyclyl,
substituted or unsubstituted heteroarylalkyl, substituted or
unsubstituted aryl, substituted or unsubstituted aralkyl; and
[0231] R.sub.1 and R.sub.2 are not .alpha.-amino acids.
[0232] In accordance with a preferred embodiment, R.sub.1 is
selected from the group formed by H, a polymer derived from
polyethylene glycol and R.sub.5--CO--, is selected from the group
formed by substituted or unsubstituted alkyl radical
C.sub.1-C.sub.24, substituted or unsubstituted alkenyl
C.sub.2-C.sub.24, substituted or unsubstituted alkynyl
C.sub.2-C.sub.24, substituted or unsubstituted cycloalkyl
C.sub.3-C.sub.24, substituted or unsubstituted cycloalkenyl
C.sub.5-C.sub.24, substituted or unsubstituted cycloalkynyl
C.sub.8-C.sub.24, substituted or unsubstituted aryl
C.sub.6-C.sub.30, substituted or unsubstituted aralkyl
C.sub.7-C.sub.24, substituted or unsubstituted heterocyclyl ring of
3-10 members, and substituted or unsubstituted heteroarylalkyl of 2
to 24 carbon atoms and 1 to 3 atoms other than carbon and an alkyl
chain of 1 to 6 carbon atoms and R.sub.5--CO is not an
.alpha.-amino acid. More preferably, R.sub.1 is selected from the
group formed by H, a polymer derived from polyethylene glycol of a
molecular weight comprised between 200 and 35000 Daltons, acetyl,
tert-butanoyl, prenyl, hexanoyl, 2-methylhexanoyl,
cyclohexanecarboxyl, octanoyl, decanoyl, lauroyl, myristoyl,
palmitoyl, stearoyl, oleoyl and linoleoyl. Even more preferably,
R.sub.1 is H, acetyl, lauroyl, myristoyl or palmitoyl. In an even
more preferable embodiment, R.sub.1 is acetyl or palmitoyl.
[0233] In accordance with another preferred embodiment, R.sub.2 is
selected from the group formed by --NR.sub.3R.sub.4, --OR.sub.3,
--SR.sub.3, wherein R.sub.3 and R.sub.4 are independently selected
from the group formed by H, a polymer derived from polyethylene
glycol, substituted or unsubstituted alkyl C.sub.1-C.sub.24,
substituted or unsubstituted alkenyl C.sub.2-C.sub.24, substituted
or unsubstituted alkynyl C.sub.2-C.sub.24, substituted or
unsubstituted cycloalkyl C.sub.3-C.sub.24, substituted or
unsubstituted cycloalkenyl C.sub.5-C.sub.24, substituted or
unsubstituted cycloalkynyl C.sub.8-C.sub.24, substituted or
unsubstituted aryl C.sub.6-C.sub.30, substituted or unsubstituted
aralkyl C.sub.7-C.sub.24, substituted or unsubstituted heterocyclyl
ring of 3-10 members, and substituted or unsubstituted
heteroarylalkyl of 2 to 24 carbon atoms and 1 to 3 atoms other than
carbon wherein the alkyl chain is of 1 to 6 carbon atoms and
--NR.sub.3R.sub.4 is not an .alpha.-amino acid. Optionally, R.sub.3
and R.sub.4 can be bound by a saturated or unsaturated
carbon-carbon bond, forming a cycle with the nitrogen atom. More
preferably R.sub.2 is --NR.sub.3R.sub.4 or --OR.sub.3. More
preferably, R.sub.3 and R.sub.4 are selected from the group formed
by H, a polymer derived from polyethylene glycol of a molecular
weight comprised between 200 and 35000 Daltons, methyl, ethyl,
hexyl, dodecyl and hexadecyl. Even more preferably R.sub.3 is H and
R.sub.4 is selected from the group formed by H, methyl, ethyl,
hexyl, dodecyl and hexadecyl. In accordance with an even more
preferred embodiment, R.sub.2 is selected from --OH and
--NH.sub.2.
[0234] In accordance with another preferred embodiment AA.sub.1 is
selected from the group formed by -Arg-, -Lys-, -Gln-, -Asn-, -Glu-
and -Asp-, AA.sub.2 is selected from the group formed by -His-,
-Gln-, -Asn-, -Glu- and -Asp-, AA.sub.3 is selected from the group
formed by -Leu- and -Phe-, AA.sub.4 is selected from the group
formed by -His-, -Lys-, -Gln- and -Leu-, AA.sub.5 is selected from
the group formed by -Arg-, -His-, -Lys-, -Gin-, -Asn-, -Glu- and
-Asp-, AA.sub.6 is selected from the group formed by -Trp- and
-Val- and AA.sub.7 is selected from the group formed by -Met-,
-MetO-- and -MetO.sub.2--. More preferably, AA.sub.4 is selected
from the group formed by -Lys- and -Leu-, and AA.sub.6 is -Trp-.
Even more preferably, n, m, p and q are 0.
[0235] In accordance with another embodiment of this invention
R.sub.1 is selected from the group formed by H, acetyl, lauroyl,
myristoyl and palmitoyl, AA.sub.1 is selected from the group formed
by -L-Arg-, -L-Lys-, -L-Gln-, -L-Asn-, -L-Glu- and -L-Asp-,
AA.sub.2 is selected from the group formed by -L-His-, -L-Gln-,
-L-Asn-, -L-Glu- and -L-Asp-, AA.sub.3 is selected from the group
formed by -L-Leu- and -L-Phe-, AA.sub.4 is selected from the group
formed by -L-His-, -L-Lys-, -L-Gln- and -L-Leu-, AA.sub.5 is
selected from the group formed by -L-Arg-, -L-His-, -L-Lys-,
-L-Gln-, -L-Asn-, -L-Glu- and -L-Asp-, AA.sub.6 is selected from
the group formed by -L-Trp- and -L-Val-, AA.sub.7 is selected from
the group formed by -L-Met-, -L-MetO-- and -L-MetO.sub.2--, and
R.sub.2 is selected from the group formed by --NR.sub.3R.sub.4 and
--OR.sub.3 where R.sub.3 and R.sub.4 are independently selected
from H, methyl, ethyl, hexyl, dodecyl and hexadecyl. More
preferably, AA.sub.4 is selected from the group formed by -L-Lys-
and -L-Leu-, and AA.sub.6 is -L-Trp-. More preferably, R.sub.1 is
acetyl or palmitoyl and R.sub.2 is --NH.sub.2. Even more
preferably, n, m, p and q are 0.
[0236] In accordance with another even more preferred embodiment
R.sub.1 is selected from the group formed by H, acetyl, lauroyl,
myristoyl and palmitoyl, AA.sub.1 is selected from the group formed
by -L-Asn-, -L-Glu- and -L-Asp-, AA.sub.2 is selected from the
group formed by -L-His- and -L-Asp-, AA.sub.3 is selected from the
group formed by -L-Leu- and -L-Phe-, AA.sub.4 is selected from the
group formed by -L-Lys-, -L-Gln- and -L-Leu-, AA.sub.5 is selected
from the group formed by -L-Arg-, -L-Gln-, -L-Asn- and -L-Asp-,
AA.sub.6 is selected from the group formed by -L-Trp-, AA.sub.7 is
selected from the group formed by -L-Met-, -L-MetO-- and
-L-MetO.sub.2-- and R.sub.2 is selected from the group formed by
--NR.sub.3R.sub.4 and --OR.sub.3 wherein R.sub.3 and R.sub.4 are
independently selected from H, methyl, ethyl, hexyl, dodecyl and
hexadecyl.
[0237] In accordance with another embodiment of this invention
R.sub.1 is selected from the group formed by H, acetyl, lauroyl,
myristoyl and palmitoyl, AA.sub.1 is -L-Glu-, AA.sub.2 is selected
from the group formed by -L-Asn-, -L-Glu-, -L-Gln- and -L-Asp-,
AA.sub.3 is -L-Leu-, AA.sub.4 is -L-Lys-, AA.sub.5 is -L-Arg-,
AA.sub.6 is -L-Trp-, AA.sub.7 is selected from the group formed by
-L-Met-, -L-MetO-- and -L-MetO.sub.2--, and R.sub.2 is selected
from the group formed by --NR.sub.3R.sub.4 and --OR.sub.3 where
R.sub.3 and R.sub.4 are independently selected from H, methyl,
ethyl, hexyl, dodecyl and hexadecyl. More preferably, R.sub.1 is
acetyl or palmitoyl and R.sub.2 is --NH.sub.2. Even more
preferably, n, m, p and q are 0.
[0238] In a preferred embodiment, the itching is selected from
itching associated with conditions, diseases and/or disorders, for
example and not restricted to, dermatitis, atopic dermatitis,
contact dermatitis, diaper dermatitis, dermatitis herpetiformis,
photodermatosis, photosensitivity, pregnancy related dermatitis,
menopause related dermatitis, eczema, sensitive skin, psoriasis,
chickenpox, herpes, herpes zoster, Netherton's syndrome, peeling
skin syndrome, lichen planus, acne, dandruff, seborrhea, seborrheic
dermatitis, alopecia, athlete's foot, candidiasis, hemorrhoids,
vaginal itching, perianal itching, anogenital itching, sunburn,
hives, pruritic otitis, itchy eyes, senile pruritus, aquagenic
pruritus, prurigo nodularis, prurigo planus, pityriasis rosea,
xerosis and dry skin, or itching associated with dialysis,
infection from human immunodeficiency virus, malignant neoplasms,
Hodgkin's disease, leukemia, myeloma, lymphoma, solid tumors,
adenocarcinoma, lung cancer, hepatic diseases, jaundice,
cholestasis, liver failure, cirrhosis, polycythemia,
hypereosinophilic syndrome, essential thrombocythemia,
myelodysplastic syndrome, iron-deficiency anemia, systemic lupus
erythematosus, endocrine diseases, thyroid diseases,
hyperthyroidism, hypothyroidism, parathyroid diseases, diabetes
mellitus, kidney diseases, kidney failure, uremia, parasitic
diseases, scabies, lice, intestinal worms, allergic reactions,
allergies to medicines, food allergies, allergies to chemical
products, exposure to poisonous plants, exposure to insect bites,
chemotherapy, stress and anxiety, among others.
[0239] In another particular embodiment, the pain is selected, for
example and not restricted to, from the group formed by acute pain,
chronic pain, nociceptive pain, neuropathic pain, inflammatory
pain, visceral pain, abdominal pain, digestive system pain,
respiratory system pain, urogenital system pain, endocrine system
pain, heart pain, pancreatic pain, liver pain, pain due to
gallstones, cholestasis, intestinal pain, stomach pain, pain due to
duodenal ulcers, pain due to esophagitis, pain due to
gastroesophageal reflux, spleen pain, blood vessel pain, thalamic
pain syndrome, irritable bowel syndrome, pain associated with
Crohn's disease, pain associated with ulcerative colitis,
diverticulitis, gastrointestinal mucositis, headache, tension-type
headache, sinusitis-associated headache, migraine, eye pain, dry
eye syndrome, post-operative pain, post-operative pain due to
surgical incisions, post-operative pain due to bone grafting,
post-operative pain due to bone substitution, post-operative pain
due to infections, post-operative pain due to limb amputations,
pain due to bone fractures, pain due to cancer, pain due to bone
cancer, pain associated with benign bone tumors, pain associated
with osteoid osteomas, pain associated with osteoblastomas, pain
due to cancer treatment, pain due to chemotherapy, pain due to
emesis, pain due to emesis as a consequence of chemotherapy
treatment, musculoskeletal pain, spastic muscle pain, fibromyalgia,
complex regional pain syndrome, psychogenic pain, neuralgic pain,
pain due to demyelinating diseases, neck pain associated with
cervical dystonia, back pain, lumbago, sciatica, neurogenic
inflammation, neuritis, causalgia, touch sensitivity, sensitivity
to cold, sensitivity to heat, cutaneous irritation, post-hair
removal cutaneous irritation, post-shaving cutaneous irritation,
psoriasis, sensitive skin, dermatitis, atopic dermatitis, contact
dermatitis, diaper dermatitis, seborrheic dermatitis, eczema,
lichen planus, burns, sunburn, arthritis, rheumatoid arthritis,
osteoarthritis, psoriatic arthritis, uveitis, pain due to nerve
lesions, neuralgia, postherpetic neuralgia, neuropathies,
peripheral neuropathies, phantom pains, allodynia, hyperalgesia,
cold hyperalgesia, pain due to carpal tunnel syndrome, burning
pain, Grierson-Gopalan syndrome (better known as burning feet
syndrome), burning mouth syndrome, paresthesias, Fabry's disease,
facial pain, trigeminal neuralgia, neuropathic pain due to
diabetes, neuropathic pain due to AIDS, orofacial pain, dental
pain, pain due to tooth extraction, pain due to wisdom tooth
extraction, tooth sensitivity to cold, tooth sensitivity to heat,
oral mucositis, temporomandibular joint pain, joint pain caused by
gout, pain associated with tattooing or tattoo removal processes,
pain due to bunions, testicular pain, myofascial pain, urinary
bladder pain, urinary tract pain, cystitis, pain due to kidney
stones, renal colic, vulvar pain, vaginal pain, post-birth pain,
menstrual pain, scrotal pain, perineal pain, pelvic pain or
hypersensitivity, cutaneous pain or irritation after surgery, after
intense pulsed light treatment (IPL), after treatment with
monochromatic pulsed light (laser), after a treatment with chemical
flaking agents or after overexposure to external aggressive agents
and pain due to chronic alcoholism, among others.
[0240] In another particular embodiment, inflammation is selected,
for example and not restricted to, from the group formed by
neurogenic inflammation, joint inflammation, tendon inflammation,
muscular inflammation, sepsis, vascular inflammation, respiratory
inflammation, chronic obstructive pulmonary disease, rhinitis,
allergic rhinitis, asthma, otitis, intestinal inflammation, Crohn's
disease, pancreatitis, hepatitis, conditions related to chronic
inflammation, to acute inflammation, nephritis, systemic lupus
erythematosus, arthritis, rheumatoid arthritis, adult and juvenile
rheumatoid arthritis, Still's disease, psoriatic arthritis,
osteoarthritis, arthritis caused by gout, rheumatoid spondylitis,
glomerulonephritis, neuritis, inflammation of the nerve tissue,
multiple sclerosis, immunological system disorders, Sjogren's
syndrome, atherosclerosis, myocarditis, pericarditis, vasculitis,
inflammatory skin conditions, psoriasis, sensitive skin,
dermatitis, atopic dermatitis, contact dermatitis, diaper
dermatitis, seborrheic dermatitis, eczema, rosacea, acne,
hyperproliferative skin disease, burns, sunburn, cutaneous
inflammation after surgery, after intense pulsed light treatment
(IPL), after treatment with monochromatic pulsed light (laser),
after a treatment with chemical flaking agents or after
overexposure to external aggressive agents, inflammation of the
vaginal mucous membranes, vulvodynia, vaginitis, inflammation of
the oral mucous membranes, gingivitis, periodontitis, inflammatory
eye diseases, uveitis, ocular and vernal conjunctivitis,
sarcoidosis, peptic ulcers, urticaria, bullous pemphigoid,
scleroderma, fibrosis, angioedema, anaphylaxis, alopecia, hepatic
cirrhosis, restenosis, polymyalgia rheumatica, seronegative
spondyloarthropathies, including ankylosing spondylitis and
Reiter's disease, dermatomyositis, inclusion body myositis,
polymyositis and lymphangioleiomyomatosis, among others.
[0241] In another particular embodiment, the neurological,
compulsive and neuropsychiatric diseases and/or disorders which are
improved by inhibition of neuronal exocytosis are selected, for
example and not restricted to, from the group formed by muscular
spasticity, dystonia, and more specifically focal dystonia such as
blepharospasm, torsion dystonia, cervical dystonia or torticollis,
laryngeal dystonia or spasmodic dysphonia, oromandibular dystonia,
extremity dystonia such as writer's cramp, musician's cramp or foot
dystonia, bruxism, facial scoliosis, hemifacial spasm, tics and/or
strabismus; segmentary dystonia, Meige's syndrome, multifocal
dystonia, hemidystonia, dopamine-responsive dystonia, Segawa's
dystonia, trembling, Parkinson's disease, nerve impingements,
Alzheimer's disease and Tourette's syndrome, among others.
[0242] In another particular embodiment, the cosmetic,
non-therapeutic treatment and/or care of the skin, is a treatment
and/or prevention, delay or hindering of aging and/or photoaging,
treatment and/or prevention, delay or hindering of wrinkles and/or
expression wrinkles, treatment and/or prevention, delay or
hindering of perspiration, treatment and/or care of skin disorders
selected, for example and not restricted to, from the group formed
by calluses and warts, among others. In an even more particular
embodiment in its treatment and/or care of the facial skin.
[0243] In another particular embodiment, the treatment and/or care
of the hair is a hair-growth stimulating and/or hair loss
prevention treatment.
[0244] In another particular embodiment, the treatment and/or
prevention, delay or hindering of perspiration, and the treatment
and/or prevention, delay or hindering of hyperhidrosis, are
treatments and/or preventions, delay or hindering of perspiration
or axillary, facial, genital, palmar or plantar hyperhidrosis.
[0245] In another aspect, the compounds of the invention can be
administered by any means that causes contact between the compounds
and the site of action in a mammal's body, preferably that of a
human being, and in the form of a composition which contains them.
The administration of the compounds of this invention is carried
out topically, transdermally, orally or parenterally. In a more
particular aspect topical or transdermal application is carried out
by iontophoresis, sonophoresis, electroporation, mechanical
pressure, osmotic pressure gradient, occlusive cure,
microinjections, by needle-free injections by means of pressure, by
microelectric patches, face masks or any combination thereof.
[0246] The frequency of the application can vary greatly, depending
on the needs of each subject, with a recommendation of an
application from once a month to ten times a day, preferably from
once a week to four times a day, more preferably from three times a
week to twice a day, even more preferably once a day.
Examples of Administration
[0247] The following specific examples provided here illustrate the
nature of this invention. These examples are included for
illustrative purposes only and should not be construed as
limitations on the invention claimed herein.
General Methodology
Abbreviations
[0248] The abbreviations used for amino acids follow the 1983
IUPAC-IUB Joint Commission on Biochemical Nomenclature
recommendations outlined in Eur. J. Biochem., (1984), 138,
9-37.
[0249] .RTM., resin; 2,6-diCIZ, 2,6-dichlorobenzyl; 2-BrZ,
2-bromobenzyloxycarbonyl; 2-ClTrt-.RTM., 2-chlorotrityl resin; Ac,
acetyl; Adpoc, 1-(1-adamantyl)-1-methylethoxy-carbonyl: Ala,
alanine; All, allyl; Alloc, allyloxycarbonyl; AM,
2-[4-aminomethyl-(2,4-dimethoxyphenyl)]phenoxyacetic acid; Arg,
arginine; Asn, asparagine; Asp, aspartic acid; Boc,
tert-butyloxycarbonyl; Bom, benzyloxymethyl; Brz,
bromobenzyloxycarbonyl; BSA, bovine serum albumin; Bzl, benzyl;
Cbz, benzyloxycarbonyl; cHx, cyclohexyl; ClZ, 2-chlorobenzyl; Cys,
cysteine; C-terminal, carboxy-terminal; DCM, dichloromethane,
methylene chloride; Dde,
N-[1-(4,4-dimethyl-2,6-dioxocyclohex-1-ylidene)ethyl; DIEA,
N,N'-diisopropylethylamine; DIPCDI, N,N'-diisopropylcarbodiimide;
Dmab,
4-(N-[1-(4,4-dimethyl-2,6-dioxocyclohexylidene)-3-methylbutyl]amino)benzy-
l; DMF, N,N-dimethylformamide; Dnp, 2,4-dinitrophenyl; EDTA,
ethylenediaminetetraacetic acid; equiv, equivalent; ESI-MS,
electrospray ionization mass spectrometry; Fm, fluorenylmethyl;
Fmoc, 9-fluorenylmethyloxycarbonyl; For, formyl; Gln, glutamine;
Glu, glutamic acid; Gly, glycine; GST, glutathione S-transferase;
His, histidine; HOAt, 1-hydroxyazabenzotriazole; HOBt,
1-hydroxybenzotriazole; HPLC, high performance liquid
chromatography; Ile, isoleucine; INCI, International Nomenclature
of Cosmetic Ingredients; IPL, Intense Pulsed Light; ivDde,
1-(4,4-dimethyl-2,6-dioxocyclohexylidene)-3-methyl-butyl; LDMA-25,
lauryldimonium hydrolyzed protein; Leu, leucine; Lys, lysine; MBHA,
p-methylbenzhydrylamine; Me, methyl; MeCN, acetonitrile; MeOH,
methanol; Met, methionine; MetO, methionine(sulfoxide); MetO.sub.2,
methionine(sulfone); MLV, multilamellar vesicles; Mtr,
4-methoxy-2,3,6-trimethylbenzenesulfonyl; Mts, mesitylenesulfonyl;
Mtt, methoxytrityl or methyltrityl; Myr, myristoyl; MW, molecular
weight; N-terminal, amino terminal; PAL,
5-(4-aminomethyl-3,5-dimethoxyphenoxy)valeric acid; Palm,
palmitoyl; Pbf, 2,2,4,6,7-pentamethyldihydrobenzofuran-5-sulfonyl;
PEG, polyethylene glycol; Phe, phenylalanine; Pmc,
2,2,5,7,8-pentamethylchroman-6-sulfonyl; pNZ,
p-nitrobenzyloxycarbonyl; Pro, proline; q.s., quantity sufficient;
q.s.p., quantity sufficient for; SEM, standard error of the mean;
Ser, serine; SNAP-25, synaptosomal-associated protein 25; SNARE,
Soluble NSF Attachment Protein Receptor; tBu, tert-butyl; Teoc,
2-(trimethylsilyl)ethyloxycarbonyl; TFA, trifluoroacetic acid; THF,
tetrahydrofuran; Thr, threonine; TIS, triisopropylsilane; Tos,
tosyl or p-toluenesulfonyl; TPA,
12-O-tetradecanoylphorbol-13-acetate; Troc,
2,2,2-trichloroethoxycarbonyl; Trp, tryptophan; Trt,
triphenylmethyl or trityl; Tyr, tyrosine; IUPAC, International
Union of Pure and Applied Chemistry; IUB, International Union of
Biochemistry; ULV, unilamellar vesicles; UVA, ultraviolet radiation
A; UVB, ultraviolet radiation B; Val, valine; VAMP,
vesicle-associated membrane proteins; Xan, xanthyl; Z,
benzyloxycarbonyl.
Chemical Synthesis
[0250] All synthetic processes were carried out in polypropylene
syringes fitted with porous polyethylene discs. All the reagents
and solvents were synthesis quality and were used without any
additional treatment. The solvents and soluble reagents were
removed by suction. The Fmoc group was removed with piperidine-DMF
(2:8, v/v) (1.times.1 min, 1.times.5 min; 5 mL/g resin)
[Lloyd-Williams P. et al., "Chemical Approaches to the Synthesis of
Peptides and Proteins", (1997), CRC, Boca Raton (FL, USA)]. Washes
between stages of deprotection, coupling, and, again, deprotection,
were carried out with DMF (3.times.1 min) each time using 10 mL
solvent/g resin. The coupling reactions were performed with 3 mL
solvent/g resin. The control of the couplings was performed by
carrying out the ninhydrin test [Kaiser E. et al., "Color test for
detection of free terminal amino groups in the solid-phase
synthesis of peptides", (1970), Anal. Biochem., 34(2), 595-598] or
chloranil test [Christensen T., "A Qualitative Test for Monitoring
Coupling Completeness in Solid Phase Peptide Synthesis Using
Chloranil", (1979), Acta Chem. Scand., 338, 763-766]. All synthetic
reactions and washes were carried out at 25.degree. C.
[0251] The HPLC chromatographic analysis was carried out with a
Shimadzu equipment (Kyoto, Japan) using a reversed-phase column
thermostatized at 30.degree. C. (250.times.4.0 mm, Kromasil
C.sub.8, 5 .mu.m, Akzo Nobel, Sweden). The elution was carried out
using a gradient of acetonitrile (+0.07% TFA) in water (+0.1% TFA)
at a flow rate of 1 mL/min and detection was carried out at 220 nm.
The electrospray ionization mass spectrometry was carried out in a
WATERS Alliance ZQ 2000 detector using a mixture of MeCN:H.sub.2O
4:1 (+0.1% TFA) as the mobile phase and a flow rate of 0.2
mL/min.
Example 1
Obtaining
Fmoc-W.sub.n--X.sub.m-AA.sub.1-AA.sub.2-AA.sub.3-AA.sub.4-AA.sub-
.5-AA.sub.6-AA.sub.7-Y.sub.p--Z.sub.q-AM-MBHA-.RTM., wherein
AA.sub.1 is -L-Glu- or -L-Asp-; AA.sub.2 is -L-Asn-, -L-Glu- or
-L-Asp-; AA.sub.3 is -L-Leu-, -L-Val- or -L-Met-; AA.sub.4 is
-L-Lys- or -L-His-; AA.sub.5 is -L-Lys-, -L-His- or -L-Arg-;
AA.sub.6 is -L-Tyr- or -L-Trp-; AA.sub.7 is -L-Met- or -L-MetO--;
and n, m, p and q are 0
[0252] 5 mmol (1 equiv) of the Fmoc-AM-MBHA resin with a
functionalization of 0.73 mmol/g were treated with piperidine-DMF
according to the described general protocol in order to remove the
Fmoc group. 2.5 equiv of Fmoc-L-Met-OH or Fmoc-L-MetO--OH were
incorporated onto the deprotected resin in the presence of 2.5
equiv of DIPCDI and 2.5 equiv of HOBt, using DMF as a solvent, for
1 hour.
[0253] The resins were then washed as described in the general
methods and the deprotection treatment of the Fmoc group was
repeated to couple the next amino acid. The Fmoc N-terminal group
was deprotected as described in the general methods and 2.5 equiv
of Fmoc-L-Tyr(tBu)-OH or Fmoc-L-Trp(Boc)-OH; 2.5 equiv of
Fmoc-L-Lys(Boc)-OH--, Fmoc-L-His(Trt)-OH or Fmoc-L-Arg(Pbf)-OH; 2.5
equiv of Fmoc-L-Lys(Boc)-OH-- or Fmoc-L-His(Trt)-OH; 2.5 equiv of
Fmoc-L-Leu-OH, Fmoc-L-Val-OH or Fmoc-L-Met-OH; 2.5 equiv of
Fmoc-L-Asn(Trt)-OH, Fmoc-L-Glu(OtBu)-OH or Fmoc-L-Asp(OtBu)-OH and
finally 2.5 equiv of Fmoc-L-Glu(OtBu)-OH or Fmoc-L-Asp(OtBu)-OH
were sequentially coupled onto the peptidyl resins for 1 hour, each
coupling in the presence of 2.5 equiv of HOBt and 2.5 equiv of
DIPCDI and using DMF as a solvent.
[0254] After the synthesis, the peptidyl resins were washed with
DCM (5.times.3 min) and dried under nitrogen stream.
Example 2
Prophetic Synthesis of
Fmoc-W.sub.n--X.sub.m-AA.sub.1-AA.sub.2-AA.sub.3-AA.sub.4-AA.sub.5-AA.sub-
.6-AA.sub.7-Y.sub.p--Z.sub.q--O-2-ClTrt-.RTM., wherein AA.sub.1 is
-L-Glu- or -L-Asp-; AA.sub.2 is -L-Gln-, -L-Asn-, -L-Glu- or
-L-Asp-; AA.sub.3 is -L-Leu-, -L-Ile-, -L-Val-, -L-Met-, -L-MetO--
or -L-MetO.sub.2--; AA.sub.4 is -L-Lys-, -L-His- or -L-Arg-;
AA.sub.5 is -L-Lys-, -L-His- or -L-Arg-; AA.sub.6 is -L-Phe-,
-L-Tyr- or -L-Trp-; AA.sub.7 is -L-Met-, -L-MetO-- or
-L-MetO.sub.2--; and n, m, p and q are 0
[0255] 8.8 mmol (1 equiv) of Fmoc-L-Met-OH, Fmoc-L-MetO--OH o
Fmoc-L-MetO.sub.2--OH dissolved in 55 mL of DCM to which 0.86 equiv
of DIEA are added, are coupled to the dry 2-chlorotrityl resin (5.5
g; 8.8 mmol). They are stirred for 5 min, after which 1.66 equiv of
DIEA are added. The mixture is allowed to react for 40 min. The
remaining chloride groups are blocked by treatment with 4.4 mL of
MeOH.
[0256] The N-terminal Fmoc group is deprotected as described in the
general methods and 2.5 equiv of Fmoc-L-Phe-OH, Fmoc-L-Tyr(tBu)-OH
or Fmoc-L-Trp(Boc)-OH are coupled onto the peptidyl resins in
presence of 2.5 equiv of DIPCDI and 2.5 equiv of HOBt, using DMF as
a solvent, for 1 hour. The resins are then washed as described in
the general methods and the deprotection treatment of the Fmoc
group is repeated to couple the next amino acid. Following the
protocols described, 2.5 equiv of Fmoc-L-Lys(Boc)-OH,
Fmoc-L-His(Trt)-OH or Fmoc-L-Arg(Pbf)-OH; 2.5 equiv of
Fmoc-L-Lys(Boc)-OH, Fmoc-L-His(Trt)-OH or Fmoc-L-Arg(Pbf)-OH; 2.5
equiv of Fmoc-L-Leu-OH, Fmoc-L-Ile-OH, Fmoc-L-Val-OH,
Fmoc-L-Met-OH, Fmoc-L-MetO--OH or Fmoc-L-MetO.sub.2--OH; 2.5 equiv
of Fmoc-L-Gln(Trt)-OH, Fmoc-L-Asn(Trt)-OH, Fmoc-L-Glu(OtBu)-OH or
Fmoc-L-Asp(OtBu)-OH and finally 2.5 equiv of Fmoc-L-Glu(OtBu)-OH or
Fmoc-L-Asp(OtBu)-OH are sequentially coupled in the presence of 2.5
equiv of HOBt and 2.5 equiv of DIPCDI in each coupling.
[0257] After the synthesis, the peptidyl resins are washed with DCM
(5.times.3 min) and dried under nitrogen stream.
Example 3
Obtaining
Fmoc-W.sub.n--X.sub.m-AA.sub.1-AA.sub.2-AA.sub.3-AA.sub.4-AA.sub-
.5-AA.sub.6-AA.sub.7-Y.sub.p--Z.sub.q-AM-MBHA-.RTM., wherein
AA.sub.1 is -L-Arg-, -L-Lys-, -L-Gln-, -L-Asn-, -L-Glu- or -L-Asp-;
AA.sub.2 is -L-His- or -L-Asp-; AA.sub.3 is -L-Leu-, -L-Met- or
-L-Phe-; AA.sub.4 is -L-Lys-, -L-His-, -L-Gln- or -L-Leu-; AA.sub.5
is -L-Arg-, -L-His-, -L-Lys-, -L-Gln-, -L-Asn-, -L-Glu- or -L-Asp-;
AA.sub.6 is -L-Tyr-, -L-Trp-, -L-Val- or -L-Arg-; AA.sub.7 is
-L-Met- or -L-MetO--; and n, m, p and q are 0
[0258] 5 mmol (1 equiv) of the Fmoc-AM-MBHA resin with a
functionalization of 0.73 mmol/g were treated with piperidine-DMF
according to the described general protocol in order to remove the
Fmoc group. 2.5 equiv of Fmoc-L-Met-OH or Fmoc-L-MetO--OH were
incorporated onto the deprotected resin in the presence of 2.5
equiv of DIPCDI and 2.5 equiv of HOBt, using DMF as a solvent, for
1 hour.
[0259] The resins were then washed as described in the general
methods and the deprotection treatment of the Fmoc group was
repeated to couple the next amino acid. The Fmoc N-terminal group
was deprotected as described in the general methods and 2.5 equiv
of Fmoc-L-Tyr(tBu)-OH, Fmoc-L-Trp(Boc)-OH, Fmoc-L-Val-OH or
Fmoc-L-Arg(Pbf)-OH; 2.5 equiv de Fmoc-L-Arg(Pbf)-OH,
Fmoc-L-His(Trt)-OH, Fmoc-L-Lys(Boc)-OH, Fmoc-L-Gln(Trt)-OH,
Fmoc-L-Asn(Trt)-OH, Fmoc-L-Glu(OtBu)-OH or Fmoc-L-Asp(OtBu)-OH; 2.5
equiv of Fmoc-L-Lys(Boc)-OH--, Fmoc-L-His(Trt)-OH,
Fmoc-L-Gln(Trt)-OH or Fmoc-L-Leu-OH; 2.5 equiv of Fmoc-L-Leu-OH,
Fmoc-L-Met-OH or Fmoc-L-Phe-OH; 2.5 equiv of Fmoc-L-His(Trt)-OH or
Fmoc-L-Asp(OtBu)-OH and finally 2.5 equiv of Fmoc-L-Arg(Pbf)-OH,
Fmoc-L-Lys(Boc)-OH, Fmoc-L-Gln(Trt)-OH, Fmoc-L-Asn(Trt)-OH,
Fmoc-L-Glu(OtBu)-OH or Fmoc-L-Asp(OtBu)-OH were sequentially
coupled onto the peptidyl resins for 1 hour, each coupling in the
presence of 2.5 equiv of HOBt and 2.5 equiv of DIPCDI and using DMF
as a solvent.
[0260] After the synthesis, the peptidyl resins were washed with
DCM (5.times.3 min) and dried under nitrogen stream.
Example 4
Prophetic Synthesis of
Fmoc-W.sub.n--X.sub.m-AA.sub.1-AA.sub.2-AA.sub.3-AA.sub.4-AA.sub.5-AA.sub-
.6-AA.sub.7-Y.sub.p--Z.sub.q--O-2-ClTrt-.RTM., wherein AA.sub.1 is
-L-Arg-, -L-His-, -L-Lys-, -L-Gln-, -L-Asn-, -L-Glu- or -L-Asp-;
AA.sub.2 is -L-His-, -L-Lys- or -L-Asp-; AA.sub.3 is -L-Leu-,
-L-Ile-, -L-Met-, -L-MetO--, -L-MetO.sub.2--, -L-Phe- or -L-Tyr-;
AA.sub.4 is -L-Lys-, -L-His-, -L-Arg-, -L-Gln-, -L-Asn-, -L-Leu-,
-L-Ile-, -L-Met-, -L-MetO--, -L-MetO.sub.2-- or -L-Val-; AA.sub.5
is -L-Arg-, -L-His-, -L-Lys-, -L-Gln-, -L-Asn-, -L-Glu- or -L-Asp-;
AA.sub.6 is -L-Phe-, -L-Tyr-, -L-Trp-, -L-Met-, -L-MetO--,
-L-MetO.sub.2--, -L-Ile-, -L-Val-, -L-His-, -L-Lys- or -L-Arg-;
AA.sub.7 is -L-Met-, -L-MetO-- or -L-MetO.sub.2--; and n, m, p and
q are 0
[0261] 8.8 mmol (1 equiv) of Fmoc-L-Met-OH, Fmoc-L-MetO--OH or
Fmoc-L-MetO.sub.2--OH dissolved in 55 mL of DCM to which 0.86 equiv
of DIEA are added, are coupled to the dry 2-chlorotrityl resin (5.5
g; 8.8 mmol). They are stirred for 5 min, after which 1.66 equiv of
DIEA are added. The mixture is allowed to react for 40 min. The
remaining chloride groups are blocked by treatment with 4.4 mL of
MeOH.
[0262] The N-terminal Fmoc group is deprotected as described in the
general methods and 2.5 equiv of Fmoc-L-Phe-OH, Fmoc-L-Tyr(tBu)-OH,
Fmoc-L-Trp(Boc)-OH, Fmoc-L-Met-OH, Fmoc-L-MetO--OH,
Fmoc-L-MetO.sub.2--OH, Fmoc-L-Ile-OH, Fmoc-L-Val-OH,
Fmoc-L-His(Trt)-OH, Fmoc-L-Lys(Boc)-OH or Fmoc-L-Arg(Pbf)-OH are
coupled onto the peptidyl resins in presence of 2.5 equiv of DIPCDI
and 2.5 equiv of HOBt, using DMF as a solvent, for 1 hour. The
resins are then washed as described in the general methods and the
deprotection treatment of the Fmoc group is repeated to couple the
next amino acid. Following the protocols described, 2.5 equiv of
Fmoc-L-Arg(Pbf)-OH, Fmoc-L-His(Trt)-OH, Fmoc-L-Lys(Boc)-OH,
Fmoc-L-Gln(Trt)-OH, Fmoc-L-Asn(Trt)-OH, Fmoc-L-Glu(OtBu)-OH or
Fmoc-L-Asp(OtBu)-OH; 2.5 equiv of Fmoc-L-Lys(Boc)-OH,
Fmoc-L-His(Trt)-OH, Fmoc-L-Arg(Pbf)-OH, Fmoc-L-Gln(Trt)-OH,
Fmoc-L-Asn(Trt)-OH, Fmoc-L-Leu-OH, Fmoc-L-Ile-OH, Fmoc-L-Met-OH,
Fmoc-L-MetO--OH, Fmoc-L-MetO.sub.2--OH or Fmoc-L-Val-OH; 2.5 equiv
of Fmoc-L-Leu-OH, Fmoc-L-Ile-OH, Fmoc-L-Met-OH, Fmoc-L-MetO--OH,
Fmoc-L-MetO.sub.2--OH, Fmoc-L-Phe-OH or Fmoc-L-Tyr(tBu)-OH; 2.5
equiv of Fmoc-L-His(Trt)-OH, Fmoc-L-Lys(Boc)-OH or
Fmoc-L-Asp(OtBu)-OH and finally 2.5 equiv of Fmoc-L-Arg(Pbf)-OH,
Fmoc-L-His(Trt)-OH, Fmoc-L-Lys(Boc)-OH, Fmoc-L-Gln(Trt)-OH,
Fmoc-L-Asn(Trt)-OH, Fmoc-L-Glu(OtBu)-OH or Fmoc-L-Asp(OtBu)-OH are
sequentially coupled in the presence of 2.5 equiv of HOBt and 2.5
equiv of DIPCDI in each coupling.
[0263] After the synthesis, the peptidyl resins are washed with DCM
(5.times.3 min) and dried under nitrogen stream.
Example 5
General Process for Cleavage of Fmoc N-Terminal Protective
Group
[0264] The N-terminal Fmoc group of the peptidyl resins obtained in
examples 1 and 3 was deprotected as described in the general
methods (20% piperidine in DMF, 1.times.5 min+1.times.20 min). The
peptidyl resins were washed with DMF (5.times.1 min), DCM
(4.times.1 min), diethyl ether (4.times.1 min) and dried under
vacuum.
[0265] Prophetically, using the same protocol the N-terminal Fmoc
group of the peptidyl resins obtained in examples 2 and 4 can be
deprotected, washed and dried.
Example 6
Process for Introducing the R.sub.1 Palmitoyl Group onto the
Peptidyl Resins Obtained in Example 5 for SEQ ID NO:25
[0266] 10 equiv of palmitic acid pre-dissolved in DMF (1 mL) were
added onto 1 mmol (1 equiv) of the peptidyl resins obtained in
Example 5 for SEQ ID NO:25, in the presence of 10 equiv of HOBt and
10 equiv of DIPCDI. They were allowed to react for 15 hours, after
which the resins were washed with THF (5.times.1 min), DCM
(5.times.1 min), DMF (5.times.1 min), MeOH (5.times.1 min), DMF
(5.times.1 min) THF (5.times.1 min), DMF (5.times.1 min), DCM
(4.times.1 min), ether (3.times.1 min), and were dried under
vacuum.
[0267] Prophetically, following the same protocol, the R.sub.1
palmitoyl group can be introduced onto the other peptidyl resins
obtained in Examples 1 to 4 after deprotecting the N-terminal
following the protocol described in Example 5.
Example 7
Process for Introducing the R.sub.1 Acetyl Group onto the Peptidyl
Resins Obtained in Example 5
[0268] 1 mmol (1 equiv) of the peptidyl resins obtained in Example
5 was treated with 25 equiv of acetic anhydride in the presence of
25 equiv of DIEA, using 5 mL of DMF as a solvent. They were allowed
to react for 30 min, after which the peptide resins were washed
with DMF (5.times.1 min), DCM (4.times.1 min), diethyl ether
(4.times.1 min) and were dried under vacuum.
[0269] Prophetically, following the same protocol the R.sub.1
acetyl group can be introduced onto the peptidyl resins
prophetically obtained in Examples 5.
Example 8
Cleavage Process of the Peptidyl Resins Obtained in Examples 6 and
7 from the Polymeric Support
[0270] 200 mg of the dried peptidyl resins obtained in Examples 6
and 7 were treated with 5 mL of TFA:TIS:H.sub.2O (90:5:5) for 2
hours at room temperature under stirring. The filtrates were
collected onto 50 mL cold diethyl ether, filtered through
polypropylene syringes fitted with porous polyethylene discs, and
washed 5 times with 50 mL diethyl ether. The final precipitates
were dried under vacuum.
[0271] HPLC analysis of the obtained peptides in gradients of MeCN
(+0.07% TFA) in H.sub.2O (+0.1% TFA) showed a purity exceeding 80%
in all cases. The identity of the peptides obtained was confirmed
by ESI-MS.
[0272] Prophetically, following the same protocol, the cleavage
from the polymeric support can be performed for the other peptidyl
resins prophetically obtained in Examples 5 to 7.
Example 9
Prophetic Cleavage Process from the Polymeric Support and
Functionalization with R.sub.2 Substituted Amine: Obtaining
Ac--W.sub.n--X.sub.m-AA.sub.1-AA.sub.2-AA.sub.3-AA.sub.4-AA.sub.5-AA.sub.-
6-AA.sub.7-Y.sub.p--Z.sub.q--NH--(CH.sub.2).sub.15--CH.sub.3,
wherein AA.sub.1 is -L-Glu- or -Asp-; AA.sub.2 is -L-Gln-, -L-Asn-,
-L-Glu- or -L-Asp-; AA.sub.3 is -L-Leu-, -L-Ile-, -L-Val-, -L-Met-,
-L-MetO--, -L-MetO.sub.2--; AA.sub.4 is -L-Lys-, -L-His- or
-L-Arg-; AA.sub.5 is -L-Lys-, -L-His- or -L-Arg-; AA.sub.6 is
-L-Phe-, -L-Tyr- or -L-Trp-; AA.sub.7 is -L-Met-, -L-MetO-- or
-L-MetO.sub.2--; and n, m, p and q are 0
[0273] The compounds
Ac--W.sub.n--X.sub.m-AA.sub.1-AA.sub.2-AA.sub.3-AA.sub.4-AA.sub.5-AA.sub.-
6-AA.sub.7-Y.sub.p--Z.sub.q--OH with fully protected side chains
are obtained by treating 150 mg of the peptidyl resins
Ac--W.sub.n--X.sub.m-AA.sub.1-AA.sub.2-AA.sub.3-AA.sub.4-AA.sub.5-AA.sub.-
6-AA.sub.7-Y.sub.p--Z.sub.q--O-2-ClTrt-.RTM. from Example 7,
previously desiccated under vacuum in the presence of KOH, with 3
mL of a 3% solution of TFA in DCM for 5 min. The filtrates are
collected onto 50 mL of cold diethyl ether and the treatment is
repeated three times. The ether solutions are evaporated to dryness
at reduced pressure and room temperature, the precipitates are
redissolved in 50% of MeCN in H.sub.2O and they are lyophilized. 10
mg of the obtained crude peptides are weighed in a flask and 3
equiv of hexadecylamine and 25 mL of anhydrous DMF are added. 2
equiv of DIPCDI are added and allowed to react under magnetic
stirring at 47.degree. C. The reactions are monitored by HPLC until
disappearance of the initial products. The solvents are evaporated
to dryness and co-evaporated twice with DCM. The obtained residues
[Ac--W.sub.n--X.sub.m-AA.sub.1-AA.sub.2-AA.sub.3-AA.sub.4-AA.sub.5-AA.sub-
.6-AA.sub.7-Y.sub.p--Z.sub.q--NH--(CH.sub.2).sub.15--CH.sub.3 with
fully protected side chains] are redissolved in 25 mL of a mixture
of TFA-DCM-anisole (49:49:2) and allowed to react for 30 min at
room temperature. 250 mL of cold diethyl ether are added, the
solvents are evaporated under reduced pressure and two additional
co-evaporations with ether are carried out. The residues are
dissolved in a mixture of 50% MeCN in H.sub.2O and lyophilized.
[0274] Purity of the obtained peptides is determined by HPLC
analysis in gradients of MeCN (+0.07% TFA) in H.sub.2O (+0.1% TFA).
The identity of the peptides obtained is confirmed by ESI-MS.
Example 10
Prophetic Cleavage Process from the Polymeric Support and
Functionalization with R.sub.2 Substituted Amine: Obtaining
Ac--W.sub.n--X.sub.m-AA.sub.1-AA.sub.2-AA.sub.3-AA.sub.4-AA.sub.5-AA.sub.-
6-AA.sub.7-Y.sub.p--Z.sub.q--NH--(CH.sub.2).sub.15--CH.sub.3,
wherein AA.sub.1 is -L-Arg-, -L-His-, -L-Lys-, -L-Gln-, -L-Asn-,
-L-Glu- or -Asp-; AA.sub.2 is -L-His-, -L-Lys- or -L-Asp-; AA.sub.3
is -L-Leu-, -L-Ile-, -L-Met-, -L-MetO--, -L-MetO.sub.2--, -L-Phe-
or -L-Tyr-; AA.sub.4 is -L-Lys-, -L-His-, -L-Arg-, -L-Gln-,
-L-Asn-, -L-Leu-, -L-Ile-, -L-Met-, -L-MetO--, -L-MetO.sub.2-- or
-L-Val-; AA.sub.5 is -L-Arg-, -L-His-, -L-Lys-, -L-Gln-, -L-Asn-,
-L-Glu- or -L-Asp-; AA.sub.6 is -L-Phe-, -L-Tyr-, -L-Trp-, -L-Met-,
-L-MetO--, -L-MetO.sub.2--, -L-Ile-, -L-Val-, -L-His-, -L-Lys- or
-L-Arg-; AA.sub.7 is -L-Met-, -L-MetO-- or -L-MetO.sub.2--; and n,
m, p and q are 0
[0275] The compounds
Ac--W.sub.n--X.sub.m-AA.sub.1-AA.sub.2-AA.sub.3-AA.sub.4-AA.sub.5-AA.sub.-
6-AA.sub.7-Y.sub.p--Z.sub.q--OH with fully protected side chains
are obtained by treating 150 mg of the prophetic peptidyl resins
Ac--W.sub.n--X.sub.m-AA.sub.1-AA.sub.2-AA.sub.3-AA.sub.4-AA.sub.5-AA.sub.-
6-AA.sub.7-Y.sub.p--Z.sub.q--O-2-ClTrt-.RTM. from Example 7,
previously desiccated under vacuum in the presence of KOH, with 3
mL of a 3% solution of TFA in DCM for 5 min. The filtrates are
collected onto 50 mL of cold diethyl ether and the treatment is
repeated three times. The ether solutions are evaporated to dryness
at reduced pressure and room temperature, the precipitates are
redissolved in 50% of MeCN in H.sub.2O and they are lyophilized. 10
mg of the obtained crude peptides are weighed in a flask and 3
equiv of hexadecylamine and 25 mL of anhydrous DMF are added. 2
equiv of DIPCDI are added and allowed to react under magnetic
stirring at 47.degree. C. The reactions are monitored by HPLC until
disappearance of the initial products. The solvents are evaporated
to dryness and co-evaporated twice with DCM. The obtained residues
[Ac--W.sub.n--X.sub.m-AA.sub.1-AA.sub.2-AA.sub.3-AA.sub.4-AA.sub.5-AA.sub-
.6-AA.sub.7-Y.sub.p--Z.sub.q--NH--(CH.sub.2).sub.15--CH.sub.3 with
fully protected side chains] are redissolved in 25 mL of a mixture
of TFA-DCM-anisole (49:49:2) and allowed to react for 30 min at
room temperature. 250 mL of cold diethyl ether are added, the
solvents are evaporated under reduced pressure and two additional
co-evaporations with ether are carried out. The residues are
dissolved in a mixture of 50% MeCN in H.sub.2O and lyophilized.
[0276] Purity of the obtained peptides can be determined by HPLC
analysis in gradients of MeCN (+0.07% TFA) in H.sub.2O (+0.1% TFA).
The identity of the peptides obtained can be confirmed by
ESI-MS.
Example 11
[0277] Following the protocols described in examples 1 to 10,
routinely varying the nature of the reagents and the peptide
sequences, the following compounds included in the scope of this
invention were also obtained.
TABLE-US-00003 TABLE 3 Identifier Average MW Experimental MW Ac-SEQ
ID NO: 1-NH.sub.2 1012.20 1012.13 .+-. 0.11 Ac-SEQ ID NO:
2-NH.sub.2 1017.18 1017.88 .+-. 0.92 Ac-SEQ ID NO: 3-NH.sub.2
919.08 918.47 .+-. 0.83 Ac-SEQ ID NO: 8-NH.sub.2 1012.24 1012.52
.+-. 0.29 Ac-SEQ ID NO: 9-NH.sub.2 999.16 999.19 .+-. 0.05 Ac-SEQ
ID NO: 12-NH.sub.2 1012.20 1012.23 .+-. 0.05 Ac-SEQ ID NO:
13-NH.sub.2 1058.28 1057.81 .+-. 0.72 Ac-SEQ ID NO: 14-NH.sub.2
1018.21 1018.08 .+-. 0.50 Ac-SEQ ID NO: 15-NH.sub.2 1002.16 1001.10
.+-. 1.88 Ac-SEQ ID NO: 16-NH.sub.2 1026.23 1026.40 .+-. 0.18
Ac-SEQ ID NO: 21-NH.sub.2 1016.24 1016.10 .+-. 0.20 Ac-SEQ ID NO:
22-NH.sub.2 998.22 998.29 .+-. 0.15 Ac-SEQ ID NO: 23-NH.sub.2
962.09 961.63 .+-. 0.68 Ac-SEQ ID NO: 24-NH.sub.2 1002.12 1002.13
.+-. 0.04 Ac-SEQ ID NO: 25-NH.sub.2 1004.13 1003.44 .+-. 0.78
Palm-SEQ ID NO: 25-NH.sub.2 1200.51 1200.55 .+-. 0.11 Ac-SEQ ID NO:
26-NH.sub.2 1017.18 1017.07 .+-. 0.15 Ac-SEQ ID NO: 27-NH.sub.2
997.19 997.51 .+-. 0.55 Ac-SEQ ID NO: 30-NH.sub.2 1031.20 1031.22
.+-. 0.19 Ac-SEQ ID NO: 31-NH.sub.2 983.16 984.16 .+-. 1.01 Ac-SEQ
ID NO: 32-NH.sub.2 1006.20 1006.23 .+-. 0.14 Ac-SEQ ID NO:
33-NH.sub.2 1058.28 1057.71 .+-. 0.72 Ac-SEQ ID NO: 34-NH.sub.2
1003.15 1001.52 .+-. 2.22 Ac-SEQ ID NO: 50-NH.sub.2 1028.20 1028.14
.+-. 0.10 Ac-SEQ ID NO: 53-NH.sub.2 1034.20 1034.14 .+-. 0.09
Ac-SEQ ID NO: 55-NH.sub.2 1018.12 1018.24 .+-. 0.49 Ac-SEQ ID NO:
56-NH.sub.2 1020.13 1020.59 .+-. 1.72 Ac-SEQ ID NO: 116-NH.sub.2
1032.23 1032.18 .+-. 0.12 Ac-SEQ ID NO: 117-NH.sub.2 1017.22
1017.18 .+-. 0.07
Example 12
Study of the Inhibition of the SNARE Complex Formation with
Detection of the Complex by ELISA
[0278] With the aim of determining the capacity of inhibition of
the SNARE complex formation by the compounds of the invention, the
competitive inhibition of the compounds compared to SNAP-25 was
studied with regards to the formation of this complex. The
proportion of SNARE complex formed was determined by the ELISA
technique, using one of the proteins from the complex bound to GST.
In a 96-well plate VAMP was immobilized (using a 0.037 .mu.M
solution) and subsequently the free spaces were blocked with BSA
(3%). Parallel to this process, SNAP-25 bound to GST (0.0185
.mu.M), syntaxin (0.037 .mu.M) and a compound of the invention (2.5
mM and 0.5 mM compounds) were incubated for 1 hour. After
incubation, the samples were transferred to the plate with
immobilized VAMP and were incubated for 1 hour to allow the
formation of the SNARE complex. Afterward, the plate was washed and
the complex was detected by a primary antibody anti-GST (Antibody
anti-GST epitope TAG, Fisher Cat. no: PA1-982A). The reading was
carried out at a wavelength of 490 nm in a TECAN GENios
spectrophotometric reader.
[0279] Table 4 shows the results of the competitive inhibition of
the formation of the SNARE complex by the compounds of the
invention versus SNAP-25. The percentage of inhibition of the
formation of the complex is inversely proportional to the quantity
of SNARE complex spectrophotometrically detected.
TABLE-US-00004 TABLE 4 % inhibition formation SNARE complex
Concentration of compound Compound 2.5 mM 0.5 mM Ac-SEQ ID NO:
1-NH.sub.2 63 33 Ac-SEQ ID NO: 2-NH.sub.2 64 26 Ac-SEQ ID NO:
3-NH.sub.2 64 31 Ac-SEQ ID NO: 8-NH.sub.2 44 11 Ac-SEQ ID NO:
12-NH.sub.2 71 20 Ac-SEQ ID NO: 13-NH.sub.2 20 Not studied Ac-SEQ
ID NO: 14-NH.sub.2 67 43 Ac-SEQ ID NO: 15-NH.sub.2 42 48 Ac-SEQ ID
NO: 22-NH.sub.2 72 18 Ac-SEQ ID NO: 23-NH.sub.2 60 10 Ac-SEQ ID NO:
24-NH.sub.2 55 41 Ac-SEQ ID NO: 25-NH.sub.2 71 40 Ac-SEQ ID NO:
27-NH.sub.2 14 Not studied Ac-SEQ ID NO: 30-NH.sub.2 71 24 Ac-SEQ
ID NO: 31-NH.sub.2 59 26 Ac-SEQ ID NO: 32-NH.sub.2 19 Not studied
Ac-SEQ ID NO: 34-NH.sub.2 85 27 Ac-SEQ ID NO: 56-NH.sub.2 Not
studied 9 Ac-SEQ ID NO: 116-NH.sub.2 69 Ac-SEQ ID NO: 117-NH.sub.2
65
Example 13
Study of the Inhibition of the SNARE Complex Formation with
Detection of the Complex by Electrophoresis
[0280] VAMP (6 .mu.M), syntaxin (6 .mu.M) and the compound of the
invention (5 mM or 1 mM compounds) were incubated for 3 hours.
Subsequently, SNAP-25 (0.6 .mu.M) was added and the mixture was
incubated for an additional 15 hours to allow the formation of the
SNARE complex. After incubation, the loading buffer (Laemli Simple
Buffer) was added and the mixture was analyzed by 10% acrylamide
SDS-PAGE in gel. The amount of complex was determined by
MediaCybernetics image analysis software Image-Pro Plus.
[0281] Table 5 shows the results of the inhibition of the formation
of the SNARE complex. The percentage of inhibition of the formation
of the complex is inversely proportional to the quantity of SNARE
complex detected.
TABLE-US-00005 TABLE 5 % inhibition formation SNARE complex
Concentration of compound Compound 5 mM 1 mM Ac-SEQ ID NO:
1-NH.sub.2 100 59 Ac-SEQ ID NO: 2-NH.sub.2 80 37 Ac-SEQ ID NO:
14-NH.sub.2 100 83 Ac-SEQ ID NO: 15-NH.sub.2 100 50 Ac-SEQ ID NO:
24-NH.sub.2 100 48 Ac-SEQ ID NO: 25-NH.sub.2 100 83 Ac-SEQ ID NO:
34-NH.sub.2 59 14
Example 14
Quantification of the Release of Noradrenaline Induced by
TPA/Ionomycin in a Neuroblastoma Cell Line by ELISA
[0282] The induction of the release of noradrenaline with TPA
(12-O-tetradecanoylphorbol-13-acetate)/Ionomycin enables direct
measurement of neuronal exocytosis. For the study of the inhibitory
effect of the compounds of the invention on the release of
noradrenaline, cells of a human neuroblastoma cell line were
pre-incubated (1.times.10.sup.6 cells/well) for 60 minutes with the
compound of the invention (1 .mu.M, 10 .mu.M, 100 .mu.M, 500 .mu.M
or 1 mM compounds), and afterward the release of noradrenaline was
induced. The release of the noradrenaline neurotransmitter was
induced by an 8 minute pre-treatment with a solution of
12-O-tetradecanoylphorbol-13-acetate (TPA) 100 nM, which mobilized
the intracellular vesicles which contained the neurotransmitter;
followed by a 5 minute incubation with TPA/Ionomycin (100 nM/10
.mu.M), which induced the release of the neurotransmitter contained
in these vesicles. The quantity of neurotransmitter released into
the growth medium was quantified by ELISA (Noradrenaline ELISA kit,
IBL International ref. RE59261), in an assay mediated by specific
antibodies against noradrenaline and completed by an enzymatic
reaction based on the reaction of alkaline phosphatase, which
resulted in a quantifiable color indication. For this, absorbance
at 405 nm was measured in Thermo Scientific Multiskan Ascent
equipment.
[0283] The blocking of the SNARE complex by the compounds of the
invention lead to an inhibition of neuronal exocytosis and
therefore, a decrease in the levels of released noradrenaline
(Table 6).
TABLE-US-00006 TABLE 6 % RELEASED NORADRENALINE TREATMENT DOSIS
Average SEM TPA/ION 100.00 3.11 Ac-SEQ ID NO: 1-NH.sub.2 1 .mu.M
96.14 5.61 10 .mu.M 93.07 3.40 100 .mu.M 79.59 2.04 500 .mu.M 49.08
1.49 1000 .mu.M 42.48 0.89 Ac-SEQ ID NO: 24- 1 .mu.M 90.63 2.38
NH.sub.2 10 .mu.M 97.06 1.76 100 .mu.M 88.95 2.15 500 .mu.M 78.11
2.92 1000 .mu.M 67.90 2.79 Ac-SEQ ID NO: 25- 1 .mu.M 99.59 1.81
NH.sub.2 10 .mu.M 94.48 1.76 100 .mu.M 74.79 3.66 500 .mu.M 48.07
3.79 1000 .mu.M 41.05 1.84 Ac-SEQ ID NO: 14- 10 .mu.M 84.96 7.24
NH.sub.2 100 .mu.M 85.97 8.38 1000 .mu.M 45.78 2.08 Ac-SEQ ID NO:
116- 1 .mu.M 87.59 4.72 NH.sub.2 10 .mu.M 83.30 4.58 100 .mu.M
62.24 3.53 500 .mu.M 52.82 2.26 1000 .mu.M 43.10 1.22 Ac-SEQ ID NO:
117- 1 .mu.M 87.99 5.20 NH.sub.2 10 .mu.M 83.11 4.82 100 .mu.M
70.76 2.77 500 .mu.M 58.37 2.82 1000 .mu.M 54.64 3.53
Example 15
Preparation of a Cosmetic Facial Composition Containing Ac-SEQ ID
NO:1-NH.sub.2
[0284] In a suitable vessel the components of phase A were
dissolved. Next, carbomer was slowly added (INCI: CARBOMER) (phase
A1), under stirring, until it was completely dissolved. The mixture
was heated to 70-75.degree. C.
[0285] In another vessel the components of phase B were mixed
together and the mixture was heated to 70-75.degree. C.
[0286] Next the mixture of phase B was added to the aqueous
solution of Phases A+A1, stirred with a turbine to form an
emulsion.
[0287] The compound Ac-SEQ ID NO:1-NH.sub.2, ALDENINE.RTM. C (INCI:
WATER (AQUA), HYDROLIZED SOY PROTEIN, HYDROLYZED WHEAT PROTEIN,
XANTHAN GUM, TRIPEPTIDE-1), aqueous solution of LEUPHASYL.RTM.
(INCI: WATER (AQUA), GLYCERIN, PENTAPEPTIDE-18, CAPRYLYL GLYCOL),
SILICONE DC 200 (INCI: DIMETHICONE) and SILICONE DC 245 (INCI:
CYCLOPENTASILOXANE) (phase C). were added stepwise under stirring
to the previous emulsion at 40.degree. C. until homogenization.
Next, perfume (INCI: FRAGRANCE (PARFUM)) (phase D), was slowly
added under stirring until homogenized.
[0288] Finally, the pH of the mixture was adjusted to 5.5-7.0 with
aqueous solution of 20% sodium hydroxide.
TABLE-US-00007 TABLE 7 Cosmetic facial composition Phase INGREDIENT
% in weight A WATER (AQUA) q.s.p. 100 A DISODIUM EDTA 0.30 A
PHENONIP .RTM. (INCI: PHENOXYETHANOL, METHYLPARABEN, ETHYLPARABEN,
BUTYLPARABEN, PROPYLPARABEN, ISOBUTYLPARABEN): PHENOXYETHANOL,
0.610 METHYLPARABEN 0.130 ETHYLPARABEN 0.033 BUTYLPARABEN 0.033
PROPYLPARABEN 0.017 ISOBUTYLPARABEN 0.017 A IMIDAZOLIDINYL UREA
0.20 A GLYCERIN 3.00 A1 CARBOMER 0.60 B MINERAL OIL (PARAFFINUM
LIQUIDUM) 7.00 B BHT 0.05 B CETYL ALCOHOL 0.80 B BEESWAX (CERA
ALBA) 0.50 B STEARYL ALCOHOL 1.50 B LIPOMULSE .RTM. 165 (INCI:
GLYCERYL STEARATE, PEG-100 STEARATE): GLYCERYL STEARATE 1.25
PEG-100 STEARATE 1.25 B DIMETHYLMETHOXY CHROMANOL 0.01 B
BENZOPHENONE-3 0.20 B ETHYLHEXYL METHOXYCINNAMATE 0.90 B CETEARYL
ALCOHOL 1.00 C Ac-SEQ ID NO: 1-NH.sub.2 0.10 C ALDENINE .RTM. C
(INCI: WATER (AQUA), HYDROLIZED SOY PROTEIN, HYDROLYZED WHEAT
PROTEIN, XANTHAN GUM, TRIPEPTIDE-1): WATER (AQUA) 1.195 HYDROLIZED
SOY PROTEIN 0.500 HYDROLYZED WHEAT PROTEIN 0.300 XANTHAN GUM 0.003
TRIPEPTIDE-1 0.002 C LEUPHASYL .RTM. SOLUTION (INCI: WATER (AQUA),
GLYCERIN, PENTAPEPTIDE-18, CAPRYLYL GLYCOL): WATER (AQUA) 4.473
GLYCERIN 0.500 PENTAPETIDE-18 0.003 CAPRYLYL GLYCOL 0.024 C
DIMETHICONE 0.10 C CYCLOPENTASILOXANE 1.00 D FRAGRANCE (PARFUM)
0.05 E 20% SODIUM HYDROXIDE q.s.p. pH 5.5-7
Example 16
Prophetic Preparation of a Cosmetic Facial Composition Containing
Ac-SEQ ID NO:24-NH.sub.2
[0289] In a suitable vessel the components from phase A are
dissolved and the mixture is heated to 70-75.degree. C.
[0290] Next the mixture of phase B is added to the aqueous solution
of Phase A under turbine stirring to form an emulsion. The emulsion
is heated to 40.degree. C. and the compound Ac-SEQ ID
NO:24-NH.sub.2, aqueous solution of ARGIRELINE.RTM. (INCI: WATER
(AQUA), ACETYL HEXAPEPTIDE-8) and ANTARCTICINE.RTM. (INCI: WATER
(AQUA), PSEUDOALTEROMONAS FERMENT EXTRACT) (phase C) is added under
stirring. Finally, the perfume (INCI: FRAGRANCE (PARFUM)) (phase D)
is added.
TABLE-US-00008 TABLE 8 Cosmetic facial composition Phase INGREDIENT
% in weight A WATER (AQUA) q.s.p. 100 A GLYCERIN 3.00 A MAGNESIUM
SULFATE 1.00 A PHENONIP .RTM. (INCI: PHENOXYETHANOL, METHYLPARABEN,
ETHYLPARABEN, BUTYLPARABEN, PROPYLPARABEN, ISOBUTYLPARABEN):
PHENOXYETANOL 0.363 METHYLPARABEN 0.077 ETHYLPARABEN 0.020
BUTYLPARABEN 0.020 PROPYLPARABEN 0.010 ISOBUTYLPARABEN 0.010 A
DISODIUM EDTA 0.15 A IMIDAZOLIDINYL UREA 0.1 B MINERAL OIL
(PARAFFINUM LIQUIDUM) 10.00 B ETHYLHEXYL COCOATE 10.00 B CETYL
PEG/PPG-10/1 DIMETHICONE 2.00 B BEESWAX (CERA ALBA) 1.50 B
HYDROGENATED CASTOR OIL 1.00 B TOCOPHERYL ACETATE 0.10 C Ac-SEQ ID
NO: 24-NH.sub.2 0.10 C ARGIRELINE .RTM. SOLUTION (INCI: WATER
(AQUA), ACETYL HEXAPEPTIDE-8): WATER (AQUA) 9.995 ACETYL
HEXAPEPTIDE-8 0.005 C ANTARCTICINE .RTM. (INCI: WATER (AQUA),
PSEUDOALTEROMONAS FERMENT EXTRACT): WATER (AQUA) 3.750
PSEUDOALTEROMONAS FERMENT 1.250 EXTRACT D FRAGRANCE (PARFUM)
0.10
Example 17
Prophetic Preparation of a Face Cream Containing Ac-SEQ ID
NO:25-NH.sub.2
[0291] In a suitable vessel pentylene glycol [INCI: PENTYLENE
GLYCOL], benzyl alcohol [INCI: BENZYL ALCOHOL], INYLINE.TM. [INCI:
ACETYL HEXAPEPTIDE-30] and the compound Ac-SEQ ID NO:25-NH.sub.2
(phase A) are dissolved in water under constant, light stirring.
Once homogenized, carbomer [INCI: CARBOMER] (phase A1) is added and
the mixture is stirred until completely dissolved. Next, potassium
cetyl phosphate [INCI: POTASSIUM CETYL PHOSPHATE] (phase A2) is
added until it is dispersed and the whole mixture is heated to
70-75.degree. C.
[0292] In a separate vessel the components of phase B are mixed
together, heated to 70-75.degree. C. and, once homogenized, phase B
is added little by little to phase A under constant stirring.
[0293] With the mixture at about 50.degree. C., phase C is slowly
added maintaining stirring. Phase D is then added until
homogenization.
[0294] Once the mixture is homogenized, the pH is adjusted to
6.0-6.5 with phase E. Finally, the perfume is added (phase F).
TABLE-US-00009 TABLE 9 Face cream composition Phase INGREDIENT % in
weight A WATER (AQUA) q.s.p. 100 A PENTYLENE GLYCOL 5.0 A BENZYL
ALCOHOL 0.40 A Ac-SEQ ID NO: 25-NH.sub.2 0.10 A ACETYL
HEXAPEPTIDE-30 0.05 A1 CARBOMER 0.50 A2 POTASSIUM CETYL PHOSPHATE
0.50 B SOYBEAN (GLYCINE SOJA) OIL 5.00 B PHYTOCREAM 2000 .RTM.
(INCI: GLYCERYL STEARATE, CETEARYL ALCOHOL, POTASSIUM PALMITOYL
HYDROLYZED WHEAT PROTEIN): GLYCERYL STEARATE 2.050 CETEARYL ALCOHOL
2.050 POTASSIUM PALMITOYL HYDROLYZED WHEAT 0.900 PROTEIN B
ETHYLHEXYL COCOATE 2.00 B PHENOXYETHANOL 0.90 C DIMETHICONE 1.00 D
SEPIGEL .TM. 305 (INCI: POLYACRYLAMIDE, WATER (AQUA), C13-14
ISOPARAFFIN, LAURETH-7) POLYACRYLAMIDE 0.400 WATER (AQUA) 0.340
C13-14 ISOPARAFFIN 0.200 LAURETH-7 0.060 E 20% SODIUM HYDROXIDE
q.s.p. pH 6.0-6.5 F FRAGRANCE (PARFUM) 0.20
Example 18
Preparation of an Antiperspirant Serum Containing Ac-SEQ ID
NO:14-NH.sub.2
[0295] In a suitable vessel Phase B was stirred until it dissolved.
In another vessel, the ingredients from phase C were heated until
completely dissolved, and phase C was added, under stirring, to
phase B.
[0296] In a separate vessel the compound Ac-SEQ ID NO:14-NH.sub.2
and PHENONIP.RTM. [INCI: PHENOXYETHANOL, METHYLPARABEN,
ETHYLPARABEN, BUTYLPARABEN, PROPYLPARABEN, ISOBUTYLPARABEN] (phase
A) were dissolved in water, under stirring.
[0297] Finally, phase A was added to the mixture of phases B+C,
under stirring until homogenized.
TABLE-US-00010 TABLE 10 Antiperspirant serum composition Phase
INGREDIENT % in weight A WATER (AQUA) 0.50 A Ac-SEQ ID NO:
14-NH.sub.2 0.50 A PHENONIP .RTM. (INCI: PHENOXYETHANOL,
METHYLPARABEN, ETHYLPARABEN, BUTYLPARABEN, PROPYLPARABEN,
ISOBUTYLPARABEN): PHENOXYETHANOL 0.36 METHYLPARABEN 0.08
ETHYLPARABEN 0.02 BUTYLPARABEN 0.02 PROPYLPARABEN 0.01
ISOBUTYLPARABEN 0.01 B SILICONE 9040 (INCI: CYCLOPENTASILOXANE,
DIMETHICONE CROSSPOLYMER): CYCLOPENTASILOXANE 43.265 DIMETHICONE
CROSSPOLYMER 7.635 CYCLOPENTASILOXANE 31.36 B FRAGRANCE (PARFUM)
0.13 C ETHYLHEXYL COCOATE 12.43 C C24-28 ALKYL DIMETHICONE 2.25 C
LECITHIN 1.38 C BHT 0.05
Example 19
Preparation of a Cosmetic Facial Composition Containing Ac-SEQ ID
NO:116-NH.sub.2
[0298] In a suitable vessel the components of phase A were
dissolved. Next, carbomer was slowly added (INCI: CARBOMER) (phase
A1), under stirring, until it was completely dissolved. The mixture
was heated to 70-75.degree. C.
[0299] In another vessel the components of phase B were mixed
together and the mixture was heated to 70-75.degree. C.
[0300] Next the mixture of phase B was added to the aqueous
solution of Phases A+A1, stirred with a turbine to form an
emulsion.
[0301] The compound Ac-SEQ ID NO:116-NH.sub.2, ALDENINE.RTM. C
(INCI: WATER (AQUA), HYDROLIZED SOY PROTEIN, HYDROLYZED WHEAT
PROTEIN, XANTHAN GUM, TRIPEPTIDE-1), aqueous solution of
LEUPHASYL.RTM. (INCI: WATER (AQUA), GLYCERIN, PENTAPEPTIDE-18,
CAPRYLYL GLYCOL), SILICONE DC 200 (INCI: DIMETHICONE) and SILICONE
DC 245 (INCI: CYCLOPENTASILOXANE) (phase C). were added stepwise
under stirring to the previous emulsion at 40.degree. C. until
homogenization. Next, perfume (INCI: FRAGRANCE (PARFUM)) (phase D),
was slowly added under stirring until homogenized.
[0302] Finally, the pH of the mixture was adjusted to 5.5-7.0 with
aqueous solution of 20% sodium hydroxide.
TABLE-US-00011 TABLE 11 Cosmetic facial composition Phase
INGREDIENT % in weight A WATER (AQUA) q.s.p. 100 A DISODIUM EDTA
0.30 A PHENONIP .RTM. (INCI: PHENOXYETHANOL, METHYLPARABEN,
ETHYLPARABEN, BUTYLPARABEN, PROPYLPARABEN, ISOBUTYLPARABEN):
PHENOXYETHANOL, 0.610 METHYLPARABEN 0.130 ETHYLPARABEN 0.033
BUTYLPARABEN 0.033 PROPYLPARABEN 0.017 ISOBUTYLPARABEN 0.017 A
IMIDAZOLIDINYL UREA 0.20 A GLYCERIN 3.00 A1 CARBOMER 0.60 B MINERAL
OIL (PARAFFINUM LIQUIDUM) 7.00 B BHT 0.05 B CETYL ALCOHOL 0.80 B
BEESWAX (CERA ALBA) 0.50 B STEARYL ALCOHOL 1.50 B LIPOMULSE .RTM.
165 (INCI: GLYCERYL STEARATE, PEG-100 STEARATE): GLYCERYL STEARATE
1.25 PEG-100 STEARATE 1.25 B DIMETHYLMETHOXY CHROMANOL 0.01 B
BENZOPHENONE-3 0.20 B ETHYLHEXYL METHOXYCINNAMATE 0.90 B CETEARYL
ALCOHOL 1.00 C Ac-SEQ ID NO: 116-NH.sub.2 0.10 C ALDENINE .RTM. C
(INCI: WATER (AQUA), HYDROLIZED SOY PROTEIN, HYDROLYZED WHEAT
PROTEIN, XANTHAN GUM, TRIPEPTIDE-1): WATER (AQUA) 1.195 HYDROLIZED
SOY PROTEIN 0.500 HYDROLYZED WHEAT PROTEIN 0.300 XANTHAN GUM 0.003
TRIPEPTIDE-1 0.002 C LEUPHASYL .RTM. SOLUTION (INCI: WATER (AQUA),
GLYCERIN, PENTAPEPTIDE-18, CAPRYLYL GLYCOL): WATER (AQUA) 4.473
GLYCERIN 0.500 PENTAPETIDE-18 0.003 CAPRYLYL GLYCOL 0.024 C
DIMETHICONE 0.10 C CYCLOPENTASILOXANE 1.00 D FRAGRANCE (PARFUM)
0.05 E 20% SODIUM HYDROXIDE q.s.p. pH 5.5-7
Example 20
Preparation of a Cosmetic Facial Composition Containing Ac-SEQ ID
NO:14-NH.sub.2
[0303] In a suitable vessel the components from phase A were
dissolved and the mixture was heated to 70-75.degree. C.
[0304] Next the mixture of phase B was added to the aqueous
solution of Phase A under turbine stirring to form an emulsion. The
emulsion was heated to 40.degree. C. and the compound Ac-SEQ ID
NO:14-NH.sub.2, aqueous solution of ARGIRELINE.RTM. (INCI: WATER
(AQUA), ACETYL HEXAPEPTIDE-8) and ANTARCTICINE.RTM. (INCI: WATER
(AQUA), PSEUDOALTEROMONAS FERMENT EXTRACT) (phase C) were added
under stirring. Finally, the perfume (INCI: FRAGRANCE (PARFUM))
(phase D) was added.
TABLE-US-00012 TABLE 12 Cosmetic facial composition Phase
INGREDIENT % in weight A WATER (AQUA) q.s.p. 100 A GLYCERIN 3.00 A
MAGNESIUM SULFATE 1.00 A PHENONIP .RTM. (INCI: PHENOXYETHANOL,
METHYLPARABEN, ETHYLPARABEN, BUTYLPARABEN, PROPYLPARABEN,
ISOBUTYLPARABEN): PHENOXYETANOL 0.363 METHYLPARABEN 0.077
ETHYLPARABEN 0.020 BUTYLPARABEN 0.020 PROPYLPARABEN 0.010
ISOBUTYLPARABEN 0.010 A DISODIUM EDTA 0.15 A IMIDAZOLIDINYL UREA
0.1 B MINERAL OIL (PARAFFINUM LIQUIDUM) 10.00 B ETHYLHEXYL COCOATE
10.00 B CETYL PEG/PPG-10/1 DIMETHICONE 2.00 B BEESWAX (CERA ALBA)
1.50 B HYDROGENATED CASTOR OIL 1.00 B TOCOPHERYL ACETATE 0.10 C
Ac-SEQ ID NO: 14-NH.sub.2 0.10 C ARGIRELINE .RTM. SOLUTION (INCI:
WATER (AQUA), ACETYL HEXAPEPTIDE-8): WATER (AQUA) 9.995 ACETYL
HEXAPEPTIDE-8 0.005 C ANTARCTICINE .RTM. (INCI: WATER (AQUA),
PSEUDOALTEROMONAS FERMENT EXTRACT): WATER (AQUA) 3.750
PSEUDOALTEROMONAS FERMENT 1.250 EXTRACT D FRAGRANCE (PARFUM)
0.10
Example 21
Preparation of a Face Cream Containing Ac-SEQ ID
NO:117-NH.sub.2
[0305] In a suitable vessel pentylene glycol [INCI: PENTYLENE
GLYCOL], benzyl alcohol [INCI: BENZYL ALCOHOL], INYLINE.TM. [INCI:
ACETYL HEXAPEPTIDE-30] and the compound Ac-SEQ ID NO:117-NH.sub.2
(phase A) were dissolved in water under constant, light stirring.
Once homogenized, carbomer [INCI: CARBOMER] (phase A1) was added
and the mixture was stirred until completely dissolved. Next,
potassium cetyl phosphate [INCI: POTASSIUM CETYL PHOSPHATE] (phase
A2) was added until it was dispersed and the whole mixture was
heated to 70-75.degree. C.
[0306] In a separate vessel the components of phase B were mixed
together, heated to 70-75.degree. C. and, once homogenized, phase B
was added little by little to phase A under constant stirring.
[0307] With the mixture at about 50.degree. C., phase C was slowly
added maintaining stirring. Phase D was then added until
homogenization.
[0308] Once the mixture was homogenized, the pH was adjusted to
6.0-6.5 with phase E. Finally, the perfume was added (phase F).
TABLE-US-00013 TABLE 13 Face cream composition Phase INGREDIENT %
in weight A WATER (AQUA) q.s.p. 100 A PENTYLENE GLYCOL 5.0 A BENZYL
ALCOHOL 0.40 A Ac-SEQ ID NO: 117-NH.sub.2 0.10 A ACETYL
HEXAPEPTIDE-30 0.05 A1 CARBOMER 0.50 A2 POTASSIUM CETYL PHOSPHATE
0.50 B SOYBEAN (GLYCINE SOJA) OIL 5.00 B PHYTOCREAM 2000 .RTM.
(INCI: GLYCERYL STEARATE, CETEARYL ALCOHOL, POTASSIUM PALMITOYL
HYDROLYZED WHEAT PROTEIN): GLYCERYL STEARATE 2.050 CETEARYL ALCOHOL
2.050 POTASSIUM PALMITOYL HYDROLYZED 0.900 WHEAT PROTEIN B
ETHYLHEXYL COCOATE 2.00 B PHENOXYETHANOL 0.90 C DIMETHICONE 1.00 D
SEPIGEL .TM. 305 (INCI: POLYACRYLAMIDE, WATER (AQUA), C13-14
ISOPARAFFIN, LAURETH-7) POLYACRYLAMIDE 0.400 WATER (AQUA) 0.340
C13-14 ISOPARAFFIN 0.200 LAURETH-7 0.060 E 20% SODIUM HYDROXIDE
q.s.p. pH 6.0-6.5 F FRAGRANCE (PARFUM) 0.20
Example 22
Prophetic Preparation of a Face Cream Containing Palm-SEQ ID
NO:1-NH.sub.2
[0309] In a suitable vessel pentylene glycol (PENTYLENE GLYCOL),
benzyl alcohol (INCI: BENZYL ALCOHOL), glycerol (INCI: GLYCEROL),
urea (INCI: UREA) and the compound Palm-SEQ ID NO:1-NH.sub.2 (phase
A) are dissolved in water. Next, carbomer (INCI: CARBOMER) (phase
A1) is slowly added, under stirring, until it is completely
dissolved. The mixture is heated to 70-75.degree. C.
[0310] The mixture of phase B is added to the aqueous solution of
Phases A+A1 under turbine stirring to form an emulsion.
[0311] The perfume (INCI: FRAGRANCE (PARFUM)) (phase C) is added to
the previous emulsion at 40.degree. C.
[0312] Finally, the pH of the mixture is adjusted to 6.0-6.5 with
aqueous solution of 20% sodium hydroxide when required.
TABLE-US-00014 TABLE 14 Face cream composition Phase INGREDIENT %
in weight A WATER (AQUA) q.s.p. 100 A PENTYLENE GLYCOL 5.0 A BENZYL
ALCOHOL 0.40 A GLYCERIN 1.00 A UREA 1.00 A Palm-SEQ ID NO:
1-NH.sub.2 0.10 A1 CARBOMER 0.60 B LIPOMULSE .RTM. 165 (INCI:
GLYCERYL STEARATE, PEG-100 STEARATE): GLYCERYL STEARATE 1.500
PEG-100 STEARATE 1.500 B CETEARETH-25 2.00 B SHEA BUTTER
(BUTYROSPERMUM PARKII) 2.00 B CAPRYLIC/CAPRIC TRIGLYCERIDE 1.00 B
ETHYLHEXYL COCOATE 7.00 B PHENOXYETHANOL 0.90 B DIMETHICONE 1.00 C
FRAGRANCE (PARFUM) 0.20 D 20% SODIUM HYDROXIDE q.s.p. pH
6.0-6.5
Example 23
Preparation of Liposomes Containing Ac-SEQ ID NO:116-NH.sub.2
[0313] Dipalmitoylphosphatidylcholine (DPPC) was weighed and
dissolved in chloroform. The solvent was evaporated to dryness
until a fine layer of phospholipid was obtained, and this layer was
hydrated by treatment with an aqueous solution which contained the
peptide Ac-SEQ ID NO:116-NH.sub.2 at the desired concentration
(containing PHENONIP.RTM.) at 55.degree. C., obtaining the MLV
liposomes. The ULV liposomes were obtained by submerging the MLV
liposomes in an ultrasound bath at 55.degree. C. for 8 cycles of 2
minutes at intervals of 5 minutes.
TABLE-US-00015 TABLE 15 INGREDIENT % IN WEIGHT WATER (AQUA) q.s.p.
100 DIPALMITOYLPHOSPHATIDYLCHOLINE 4.00 Ac-SEQ ID NO: 116-NH.sub.2
0.20 PHENONIP .RTM. (INCI: PHENOXYETHANOL, METHYLPARABEN,
ETHYLPARABEN, BUTYLPARABEN, PROPYLPARABEN, ISOBUTYLPARABEN):
ISOBUTYLPARABEN 0.01 PHENOXYETHANOL 0.36 METHYLPARABEN 0.08
ETHYLPARABEN 0.02 BUTYLPARABEN 0.02 PROPYLPARABEN 0.01
Example 24
Preparation of Coacervation Capsules Containing the Compound
Palm-SEQ ID NO:25-NH.sub.2
a) Preparation of an Emulsion of the Compound Palm-SEQ ID
NO:25-NH.sub.2
[0314] In a suitable vessel the peptide was dissolved in water
(phase A) heating the mixture to 70.degree. C. In a separate vessel
soybean oil [INCI: SOYBEAN (GLYCINE SOJA) OIL], Abil EM 90 [INCI:
CETYL PEG/PPG-10/1 DIMETHICONE] and Span 65 [INCI: SORBITAN
TRISTEARATE] (phase B) were mixed together, heating the mixture to
80.degree. C. until the Span 65 dissolved. Once melted, phase A was
added to phase B slowly under intense stirring with a turbine. Once
the components were mixed together, the mixture was stirred until
it reached room temperature.
TABLE-US-00016 TABLE 16 Phase INGREDIENT % in weight A PURIFIED
WATER 56.00 B SOYBEAN (GLYCINE SOJA) OIL 33.00 B CETYL PEG/PPG-10/1
DIMETHICONE 5.00 B SORBITAN TRISTEARATE 4.00 A Palm-SEQ ID NO:
25-NH.sub.2 2.00
b) Preparation of a Microfluidized Emulsion of the Compound
Palm-SEQ ID NO:25-NH.sub.2
[0315] The components of phase A were mixed together in water:
Zemea Propanediol [INCI: PROPANEDIOL], phenoxyethanol [INCI:
PHENOXYETHANOL], Structure XL [INCI: HYDROXYPROPYL STARCH
PHOSPHATE], Amigel [INCI: SCLEROTIUM GUM] and powdered hyaluronic
acid [INCI: SODIUM HYALURONATE], the mixture was heated to
70.degree. C. under stirring. In another vessel, the emulsion from
section a), and the components of phase B: Massocare HD [INCI:
ISOHEXADECANE], Arlacel [INCI: SORBITAN SESQUIOLEATE],
LIPOCHROMAN.TM. [INCI: DIMETHYLMETHOXY CHROMANOL] were mixed
together, and the mixture was heated to 80.degree. C. under
stirring.
[0316] Once this temperature was reached, phase B was added to
phase A very slowly under intense stirring with a turbine.
[0317] The sample was passed, without cooling, through a
microfluidizer for three cycles at an entrance pressure of 80 bar
and an exit pressure of 15000 psi, maintaining the operating
temperature between 65 and 75.degree. C. Once microfluidized, the
emulsion was stirred with a rotor until room temperature was
reached.
TABLE-US-00017 TABLE 17 Phase INGREDIENT % in weight A WATER (AQUA)
70.36 B Emulsion section a) 10.95 B ISOHEXADECANE 5.48 A
PROPANEDIOL 5.48 B SORBITAN SESQUIOLEATE 4.38 A PHENOXYETHANOL 2.85
A HYDROXYPROPYL STARCH PHOSPHATE 0.33 A SCLEROTIUM GUM 0.11 B
DIMETHYLMETHOXY CHROMANOL 0.05 A SODIUM HYALURONATE 0.01
c) Obtaining Coacervate Capsules Containing the Compound Palm-SEQ
ID NO:25-NH.sub.2
[0318] In a vessel the emulsion from section b) (phase A) was
weighed. In another vessel Sensomer CI 50 [INCI: WATER (AQUA);
STARCH HYDROXYPROPYLTRIMONIUM CHLORIDE; UREA; SODIUM LACTATE;
SODIUM CHLORIDE; SODIUM BENZOATE] was dissolved in water (phase B).
Phase B was added to phase A under intense stirring.
[0319] Amigel [INCI: SCLEROTIUM GUM] (phase C) was added to the
previous mixture very slowly and under intense stirring. The
mixture was stirred for 2 hours to obtain good hydration of the
gum.
[0320] Next, Structure XL [INCI: HYDROXYPROPYL STARCH PHOSPHATE]
(phase D) was added, maintaining the stirring for another hour to
obtain the complete hydration of the biopolymers added.
[0321] Finally, Sepigel.TM. 305 [INCI: POLYACRYLAMIDE; WATER
(AQUA); C13-14 ISOPARAFFIN; LAURETH-7] (phase E) was added,
maintaining the stirring until a homogenous suspension was
obtained. The average size of the capsules in suspension obtained
determined by Dynamic Laser Light Scattering was approximately 300
nm.
TABLE-US-00018 TABLE 18 Phase INGREDIENT % in weight A Emulsion
section b) 91.30 B WATER (AQUA) 6.00 D HYDROXYPROPYL STARCH
PHOSPHATE 1.50 C SCLEROTIUM GUM 0.75 E SEPIGEL .TM. 305 (INCI:
POLYACRYLAMIDE, WATER (AQUA), C13-14 ISOPARAFFIN, LAURETH-7):
POLYACRYLAMIDE 0.10 WATER (AQUA) 0.085 C13-14 ISOPARAFFIN 0.05
LAURETH-7 0.015 B SENSOMER CI 50 [INCI: WATER (AQUA); STARCH
HYDROXYPROPYLTRIMONIUM CHLORIDE; UREA; SODIUM LACTATE; SODIUM
CHLORIDE; SODIUM BENZOATE]: WATER (AQUA) 0.137 STARCH
HYDROXYPROPYLTRIMONIUM 0.048 CHLORIDE UREA 0.006 SODIUM LACTATE
0.004 SODIUM CHLORIDE 0.004 SODIUM BENZOATE 0.001
[0322] The Sequence listing entitled 788774.sub.--1.txt filed
herewith is incorporated by reference herein in its entirety.
[0323] It will be appreciated that variants of the above-disclosed
and other features and functions, or alternatives thereof, may be
combined into many other different systems or applications. Various
presently unforeseen or unanticipated alternatives, modifications,
variations or improvements therein may be subsequently made by
those skilled in the art which are also intended to be encompassed
by the following claims.
Sequence CWU 1
1
15917PRTArtificial SequenceSynthetic peptide 1Glu His Leu Lys Gln
Trp Met 1 5 27PRTArtificial SequenceSynthetic peptide 2Gln Asp Phe
Leu His Trp Met 1 5 37PRTArtificial SequenceSynthetic peptide 3Gln
His Leu His Asn Val Met 1 5 47PRTArtificial SequenceSynthetic
peptide 4Lys Asp Ile Lys Asn Trp Met 1 5 57PRTArtificial
SequenceSynthetic peptide 5Asp His Leu Lys Gln Phe Met 1 5
67PRTArtificial SequenceSynthetic peptide 6Glu His Met Lys Gln Tyr
Met 1 5 77PRTArtificial SequenceSynthetic peptide 7Lys Asp Leu Lys
Glu Trp Met 1 5 87PRTArtificial SequenceSynthetic peptide 8Glu His
Leu Lys Lys Trp Met 1 5 97PRTArtificial SequenceSynthetic peptide
9Asp His Leu Lys Glu Trp Met 1 5 107PRTArtificial SequenceSynthetic
peptide 10Lys Asp Leu Arg Arg Trp Met 1 5 117PRTArtificial
SequenceSynthetic peptide 11Asp Asp Leu Lys Arg Tyr Met 1 5
127PRTArtificial SequenceSynthetic peptide 12Gln His Leu Lys Glu
Trp Met 1 5 137PRTArtificial SequenceSynthetic peptide 13Arg His
Phe Leu Gln Trp Met 1 5 147PRTArtificial SequenceSynthetic peptide
14Glu Asp Leu Lys Arg Trp Met 1 5 157PRTArtificial
SequenceSynthetic peptide 15Asn His Phe Leu Asn Trp Met 1 5
167PRTArtificial SequenceSynthetic peptide 16Arg His Leu Lys Asp
Trp Met 1 5 177PRTArtificial SequenceSynthetic peptide 17Asp His
Phe Asn Gln Arg Met 1 5 187PRTArtificial SequenceSynthetic peptide
18Glu Asp Phe Gln Gln His Met 1 5 197PRTArtificial
SequenceSynthetic peptide 19Glu His Phe Leu Glu Phe Met 1 5
207PRTArtificial SequenceSynthetic peptide 20Lys His Leu Gln Gln
Ile Met 1 5 217PRTArtificial SequenceSynthetic peptide 21Asn His
Phe Leu Lys Trp Met 1 5 227PRTArtificial SequenceSynthetic peptide
22Asp His Leu Lys Lys Trp Met 1 5 237PRTArtificial
SequenceSynthetic peptide 23Asn Asp Leu Lys Asp Trp Met 1 5
247PRTArtificial SequenceSynthetic peptide 24Asp His Phe Gln Gln
Arg Met 1 5 257PRTArtificial SequenceSynthetic peptide 25Asp His
Phe Leu Asp Trp Met 1 5 267PRTArtificial SequenceSynthetic peptide
26Asp His Phe Leu Gln Trp Met 1 5 277PRTArtificial
SequenceSynthetic peptide 27Gln His Leu Lys Asn Trp Met 1 5
287PRTArtificial SequenceSynthetic peptide 28Arg Asp Leu Ile Arg
Lys Met 1 5 297PRTArtificial SequenceSynthetic peptide 29Asn His
Phe Asn Asn Lys Met 1 5 307PRTArtificial SequenceSynthetic peptide
30Glu His Phe Leu Gln Trp Met 1 5 317PRTArtificial
SequenceSynthetic peptide 31Asn His Leu Lys Asn Trp Met 1 5
327PRTArtificial SequenceSynthetic peptide 32Asn His Leu Lys His
Trp Met 1 5 337PRTArtificial SequenceSynthetic peptide 33Gln His
Phe Leu Arg Trp Met 1 5 347PRTArtificial SequenceSynthetic peptide
34Asp His Phe Leu Asn Trp Met 1 5 357PRTArtificial
SequenceSynthetic peptide 35Glu His Leu Arg Gln Trp Met 1 5
367PRTArtificial SequenceSynthetic peptide 36Glu His Ile Lys Gln
Trp Met 1 5 377PRTArtificial SequenceSynthetic peptide 37Glu His
Met Arg Gln Val Met 1 5 387PRTArtificial SequenceSynthetic peptide
38Glu His Ile Met His Trp Met 1 5 397PRTArtificial
SequenceSynthetic peptide 39Asp His Met Asn Arg Val Met 1 5
407PRTArtificial SequenceSynthetic peptide 40Asp Asp Met Lys Arg
Trp Met 1 5 417PRTArtificial SequenceSynthetic peptide 41Asn His
Tyr Leu Asn Trp Met 1 5 427PRTArtificial SequenceSynthetic peptide
42Gln His Phe Ile Asn Arg Met 1 5 437PRTArtificial
SequenceSynthetic peptide 43Asn His Phe Val Asn Tyr Met 1 5
447PRTArtificial SequenceSynthetic peptide 44Gln His Phe Leu Asn
Phe Met 1 5 457PRTArtificial SequenceSynthetic peptide 45Glu His
Tyr Gln Gln Arg Met 1 5 467PRTArtificial SequenceSynthetic peptide
46Arg His Leu Val Gln Met Met 1 5 477PRTArtificial
SequenceSynthetic peptide 47His His Leu Ile Gln Met Met 1 5
487PRTArtificial SequenceSynthetic peptide 48His Asp Ile Val Arg
His Met 1 5 497PRTArtificial SequenceSynthetic peptide 49Lys His
Met Met Gln Ile Met 1 5 507PRTArtificial SequenceSynthetic peptide
50Glu His Leu Lys Gln Trp Xaa 1 5 517PRTArtificial
SequenceSynthetic peptide 51Gln Asp Phe Leu His Trp Xaa 1 5
527PRTArtificial SequenceSynthetic peptide 52Gln His Leu His Asn
Val Xaa 1 5 537PRTArtificial SequenceSynthetic peptide 53Glu Asp
Leu Lys Arg Trp Xaa 1 5 547PRTArtificial SequenceSynthetic peptide
54Asn His Phe Leu Asn Trp Xaa 1 5 557PRTArtificial
SequenceSynthetic peptide 55Asp His Phe Gln Gln Arg Xaa 1 5
567PRTArtificial SequenceSynthetic peptide 56Asp His Phe Leu Asp
Trp Xaa 1 5 577PRTArtificial SequenceSynthetic peptide 57Asp His
Phe Leu Asn Trp Xaa 1 5 587PRTArtificial SequenceSynthetic peptide
58Glu His Leu Lys Gln Trp Xaa 1 5 597PRTArtificial
SequenceSynthetic peptide 59Glu Asp Leu Lys Arg Trp Xaa 1 5
607PRTArtificial SequenceSynthetic peptide 60Asp His Phe Gln Gln
Arg Xaa 1 5 617PRTArtificial SequenceSynthetic peptide 61Asp His
Phe Leu Asp Trp Xaa 1 5 628PRTArtificial SequenceSynthetic peptide
62Glu Glu His Leu Lys Gln Trp Met 1 5 638PRTArtificial
SequenceSynthetic peptide 63Glu His Leu Lys Gln Trp Met Arg 1 5
648PRTArtificial SequenceSynthetic peptide 64Arg Gln Asp Phe Leu
His Trp Met 1 5 658PRTArtificial SequenceSynthetic peptide 65Gln
Asp Phe Leu His Trp Met His 1 5 668PRTArtificial SequenceSynthetic
peptide 66Asp Gln His Leu His Asn Val Met 1 5 678PRTArtificial
SequenceSynthetic peptide 67Gln His Leu His Asn Val Met Lys 1 5
688PRTArtificial SequenceSynthetic peptide 68Glu Gln His Leu Lys
Glu Trp Met 1 5 698PRTArtificial SequenceSynthetic peptide 69Gln
His Leu Lys Glu Trp Met Arg 1 5 708PRTArtificial SequenceSynthetic
peptide 70Asp Glu Asp Leu Lys Arg Trp Met 1 5 718PRTArtificial
SequenceSynthetic peptide 71Glu Asp Leu Lys Arg Trp Met Lys 1 5
728PRTArtificial SequenceSynthetic peptide 72Glu Asn His Phe Leu
Asn Trp Met 1 5 738PRTArtificial SequenceSynthetic peptide 73Asn
His Phe Leu Asn Trp Met His 1 5 748PRTArtificial SequenceSynthetic
peptide 74Asp Asp His Leu Lys Lys Trp Met 1 5 758PRTArtificial
SequenceSynthetic peptide 75Asp His Leu Lys Lys Trp Met Arg 1 5
768PRTArtificial SequenceSynthetic peptide 76Asp Asp His Phe Gln
Gln Arg Met 1 5 778PRTArtificial SequenceSynthetic peptide 77Asp
His Phe Gln Gln Arg Met Arg 1 5 788PRTArtificial SequenceSynthetic
peptide 78Glu Asp His Phe Leu Asp Trp Met 1 5 798PRTArtificial
SequenceSynthetic peptide 79Asp His Phe Leu Asp Trp Met Lys 1 5
808PRTArtificial SequenceSynthetic peptide 80Glu Asn His Leu Lys
Asn Trp Met 1 5 818PRTArtificial SequenceSynthetic peptide 81Asn
His Leu Lys Asn Trp Met His 1 5 828PRTArtificial SequenceSynthetic
peptide 82Asp Asp His Phe Leu Asn Trp Met 1 5 838PRTArtificial
SequenceSynthetic peptide 83Asp His Phe Leu Asn Trp Met Arg 1 5
848PRTArtificial SequenceSynthetic peptide 84Glu His Leu Lys Gln
Trp Xaa Arg 1 5 858PRTArtificial SequenceSynthetic peptide 85Asp
Glu Asp Leu Lys Arg Trp Xaa 1 5 868PRTArtificial SequenceSynthetic
peptide 86Asn His Phe Leu Asn Trp Xaa Arg 1 5 878PRTArtificial
SequenceSynthetic peptide 87Asp His Phe Gln Gln Arg Xaa Arg 1 5
888PRTArtificial SequenceSynthetic peptide 88Asp His Phe Leu Asp
Trp Xaa Lys 1 5 898PRTArtificial SequenceSynthetic peptide 89Glu
His Leu Lys Gln Trp Xaa Arg 1 5 908PRTArtificial SequenceSynthetic
peptide 90Asp Glu Asp Leu Lys Arg Trp Xaa 1 5 918PRTArtificial
SequenceSynthetic peptide 91Asp His Phe Gln Gln Arg Xaa Arg 1 5
928PRTArtificial SequenceSynthetic peptide 92Asp His Phe Leu Asp
Trp Xaa Lys 1 5 939PRTArtificial SequenceSynthetic peptide 93Glu
Glu His Leu Lys Gln Trp Met Arg 1 5 949PRTArtificial
SequenceSynthetic peptide 94Glu His Leu Lys Gln Trp Met Arg Arg 1 5
959PRTArtificial SequenceSynthetic peptide 95Asp Glu Gln His Leu
His Asn Val Met 1 5 969PRTArtificial SequenceSynthetic peptide
96Gln His Leu His Asn Val Met Arg Arg 1 5 979PRTArtificial
SequenceSynthetic peptide 97Glu Glu Asp Leu Lys Arg Trp Met Met 1 5
989PRTArtificial SequenceSynthetic peptide 98Asp Glu Glu Asp Leu
Lys Arg Trp Met 1 5 999PRTArtificial SequenceSynthetic peptide
99Gln Arg Asn His Phe Leu Asn Trp Met 1 5 1009PRTArtificial
SequenceSynthetic peptide 100Asn His Phe Leu Asn Trp Met Met Arg 1
5 1019PRTArtificial SequenceSynthetic peptide 101Glu Asp His Phe
Gln Gln Arg Met Leu 1 5 1029PRTArtificial SequenceSynthetic peptide
102Asp Asp His Phe Gln Gln Arg Met Arg 1 5 1039PRTArtificial
SequenceSynthetic peptide 103Asp His Phe Leu Asp Trp Met Arg Arg 1
5 1049PRTArtificial SequenceSynthetic peptide 104Asp His Asp His
Phe Leu Asp Trp Met 1 5 1059PRTArtificial SequenceSynthetic peptide
105Glu His Phe Leu Gln Trp Met Arg Met 1 5 1069PRTArtificial
SequenceSynthetic peptide 106Asp Glu His Phe Leu Gln Trp Met Val 1
5 1079PRTArtificial SequenceSynthetic peptide 107Glu His Leu Lys
Gln Trp Xaa Arg Lys 1 5 1089PRTArtificial SequenceSynthetic peptide
108Gln Arg Asn His Phe Leu Asn Trp Xaa 1 5 1099PRTArtificial
SequenceSynthetic peptide 109Glu His Leu Lys Gln Trp Xaa Arg Lys 1
5 1109PRTArtificial SequenceSynthetic peptide 110Gln Arg Asn His
Phe Leu Asn Trp Xaa 1 5 1119PRTArtificial SequencePeptide derived
from bovine bactenecin 111Trp Lys Lys His Leu Leu Lys Ile Met 1 5
1127PRTArtificial SequenceSynthetic peptide 112Glu Asp Val Lys Arg
Trp Met 1 5 1137PRTArtificial SequenceSynthetic peptide 113Glu Gln
Leu Lys Arg Trp Met 1 5 1147PRTArtificial SequenceSynthetic peptide
114Asp Asp Val Lys Lys Phe Met 1 5 1157PRTArtificial
SequenceSynthetic peptide 115Asp Asn Leu Lys Arg Phe Met 1 5
1167PRTArtificial SequenceSynthetic peptide 116Glu Glu Leu Lys Arg
Trp Met 1 5 1177PRTArtificial SequenceSynthetic peptide 117Glu Asn
Leu Lys Arg Trp Met 1 5 1187PRTArtificial SequenceSynthetic peptide
118Glu Asp Val Arg Arg Trp Met 1 5 1197PRTArtificial
SequenceSynthetic peptide 119Glu His Phe Leu Glu Trp Met 1 5
1207PRTArtificial SequenceSynthetic peptide 120Asp Glu Ile His Lys
Trp Met 1 5 1217PRTArtificial SequenceSynthetic peptide 121Glu Asn
Leu Arg Arg Trp Met 1 5 1227PRTArtificial SequenceSynthetic peptide
122Asp Asn Leu His Lys Tyr Met 1 5 1237PRTArtificial
SequenceSynthetic peptide 123Glu Gln Ile Lys His Phe Met 1 5
1247PRTArtificial SequenceSynthetic peptide 124Asp Asn Met Arg Arg
Phe Met 1 5 1257PRTArtificial SequenceSynthetic peptide 125Glu Glu
Met Lys Arg Trp Met 1 5 1267PRTArtificial SequenceSynthetic peptide
126Asp Gln Met Lys His Tyr Met 1 5 1277PRTArtificial
SequenceSynthetic peptide 127Glu Glu Leu Lys Arg Trp Xaa 1 5
1287PRTArtificial SequenceSynthetic peptide 128Asp Asp Val His Arg
Trp Xaa 1 5 1297PRTArtificial SequenceSynthetic peptide 129Glu Asn
Leu Lys Arg Trp Xaa 1 5 1307PRTArtificial SequenceSynthetic peptide
130Asp Glu Val Arg His Tyr Xaa 1 5 1317PRTArtificial
SequenceSynthetic peptide 131Glu Glu Leu Lys Arg Trp Xaa 1 5
1327PRTArtificial SequenceSynthetic peptide 132Glu Asn Leu Lys Arg
Trp Xaa 1 5 1337PRTArtificial SequenceSynthetic peptide 133Asp Gln
Ile Arg Lys Phe Xaa 1 5 1348PRTArtificial SequenceSynthetic peptide
134Glu Glu Gln Leu Lys Arg Trp Met 1 5 1358PRTArtificial
SequenceSynthetic peptide 135Glu Gln Leu Lys Arg Trp Met Arg 1 5
1368PRTArtificial SequenceSynthetic peptide 136Arg Glu Glu Leu Lys
Arg Trp Met 1 5 1378PRTArtificial SequenceSynthetic peptide 137Glu
Glu Leu Lys Arg Trp Met His 1 5 1388PRTArtificial SequenceSynthetic
peptide 138Asp Glu Asn Leu Lys Arg Trp Met 1 5 1398PRTArtificial
SequenceSynthetic peptide 139Glu Asn Leu Lys Arg Trp Met Lys 1 5
1408PRTArtificial SequenceSynthetic peptide 140Glu Asp Asn Leu Lys
Arg Phe Met 1 5 1418PRTArtificial SequenceSynthetic peptide 141Asp
Asn Leu Lys Arg Phe Met Arg 1 5 1428PRTArtificial SequenceSynthetic
peptide 142Glu Glu Gln Ile Lys His Phe Met 1 5 1438PRTArtificial
SequenceSynthetic peptide 143Glu Gln Ile Lys His Phe Met His 1 5
1448PRTArtificial SequenceSynthetic peptide 144Glu Glu Leu Lys Arg
Trp Xaa Arg 1 5 1458PRTArtificial SequenceSynthetic peptide 145Glu
Asn Leu Lys Arg Trp Xaa Arg 1 5 1468PRTArtificial SequenceSynthetic
peptide 146Glu Glu Leu Lys Arg Trp Xaa Arg 1 5 1478PRTArtificial
SequenceSynthetic peptide 147Glu Asn Leu Lys Arg Trp Xaa Arg 1 5
1489PRTArtificial SequenceSynthetic peptide 148Glu Glu Gln Leu Lys
Arg Trp Met Arg 1 5 1499PRTArtificial SequenceSynthetic peptide
149Glu Gln Leu Lys Arg Trp Met Arg Arg 1 5 1509PRTArtificial
SequenceSynthetic peptide 150Asp Glu Glu Leu Lys Arg Trp Met Arg 1
5 1519PRTArtificial SequenceSynthetic peptide 151Glu Glu Leu Lys
Arg Trp Met Arg Arg 1 5 1529PRTArtificial SequenceSynthetic peptide
152Gln Arg Glu Asn Leu Lys Arg Trp Met 1 5 1539PRTArtificial
SequenceSynthetic peptide 153Glu Asn Leu Lys Arg Trp Met Met Arg 1
5 1549PRTArtificial SequenceSynthetic peptide 154Gln Arg Glu Gln
Ile Lys His Phe Met 1 5 1559PRTArtificial SequenceSynthetic peptide
155Glu Gln Ile Lys His Phe Met Met Arg 1 5 1569PRTArtificial
SequenceSynthetic peptide 156Glu Glu Leu Lys Arg Trp Xaa Arg Lys 1
5 1579PRTArtificial SequenceSynthetic peptide 157Gln Arg Glu Asn
Leu Lys Arg Trp Xaa 1 5 1589PRTArtificial SequenceSynthetic peptide
158Glu Asn Leu Lys Arg Trp Xaa Arg Lys 1 5 1599PRTArtificial
SequenceSynthetic peptide 159Gln Arg Glu Glu Leu Lys Arg Trp Xaa 1
5
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